Next Article in Journal
Editorial on the Special Issue “Heme Metabolism and Porphyria”
Previous Article in Journal
Impact of Pericoronary Microbiota Composition on Course of Recovery after Third Molar Alveotomy
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders

by
Irina Balan
1,2,
Giorgia Boero
3,†,
Samantha Lucenell Chéry
1,4,†,
Minna H. McFarland
1,4,†,
Alejandro G. Lopez
1,5 and
A. Leslie Morrow
1,2,6,*
1
Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2
Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
3
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
4
Neuroscience Curriculum, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
5
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
6
Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Life 2024, 14(5), 582; https://doi.org/10.3390/life14050582
Submission received: 11 March 2024 / Revised: 18 April 2024 / Accepted: 28 April 2024 / Published: 30 April 2024

Abstract

:
Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders.

1. Introduction

In recent years, the critical role of inflammation in neurological and psychiatric disorders has gained increasing recognition, stimulating interest in therapeutic agents capable of modulating these processes [1,2,3,4,5,6]. Among these agents, endogenous neuroactive steroids have emerged as significant candidates. Initially identified for their influence on gamma-aminobutyric acid type A (GABAA) receptors, such as allopregnanolone ((3α,5α)3-hydroxypregnan-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP)), pregnanolone, and tetrahydrodeoxycorticosterone ([3α,5α]-3,21-dihydroxypregnan-20-one; 3α,5α-THDOC; THDOC), ongoing research has revealed their multifaceted functions and potential to influence central nervous system (CNS) disorders [7,8,9,10,11,12,13].
Neuroactive steroids are synthesized within both endocrine glands and the brain. In the brain, neurons are the primary producers of neurosteroids [14,15,16,17,18,19,20]. Neuroactive steroids, synthesized from cholesterol, can be classified into three categories: pregnane, androstane, and sulfated neuroactive steroids. Pregnanes, including allopregnanolone, pregnanolone, and 3α,5α-THDOC, act as positive modulators of GABAA receptor subtypes. These compounds enhance inhibitory neurotransmission mediated by GABAA receptors, leading to anxiolysis, sedation, anti-convulsant activity, and the enhancement of inhibitory circuits in the brain [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. Importantly, their anti-inflammatory actions are distinct from their GABAergic mechanisms [36,37,38].
Preclinical and clinical studies have highlighted reduced levels of pregnane neuroactive steroids, such as pregnenolone and allopregnanolone, in conditions like stress, depression, post-traumatic stress disorder (PTSD), and alcohol use disorder (AUD) [39,40,41,42,43,44,45,46,47]. To address these deficits, researchers explored the therapeutic potential of pregnane steroids. Allopregnanolone and its precursors, pregnenolone and progesterone, have shown promise in animal models of AUD, chronic stress-induced depression, traumatic brain injury (TBI), multiple sclerosis (MS), and Alzheimer’s disease (AD) [48,49,50,51,52,53,54,55,56]. In clinical studies, progesterone has demonstrated efficacy in TBI and cocaine craving, while pregnenolone has shown benefits in alcohol and cannabis use disorders, and allopregnanolone has been effective in treating postpartum depression (PPD) [57,58,59,60,61,62,63,64,65,66].
Recent studies have highlighted the ability of pregnane neuroactive steroids to counteract inflammatory signals triggered by toll-like receptor (TLR) activation, reducing the production of inflammatory mediators. Clinical observations further support the therapeutic potential of compounds like brexanolone, a Food and Drug Administration (FDA)-approved intravenous formulation of allopregnanolone, in conditions such as PPD, attributed to their inhibition of TLR inflammatory pathways [36,37,54,64,67,68,69,70,71,72,73,74,75,76]. Furthermore, recent research has elucidated the trophic and anti-inflammatory properties demonstrated by pregnane neurosteroids, which stimulate the production of crucial trophic proteins and anti-inflammatory cytokines [77,78,79,80,81,82,83].
Moreover, research has examined the roles of androstane neuroactive steroids, encompassing dehydroepiandrosterone (DHEA) and androstenediol (ADIOL), as well as estrogens and androgens, in immune and neuroimmune regulation. The interplay between androstane neuroactive steroids and neuropsychiatric conditions is complex and influenced by factors such as sex, age, and individual differences [84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105]. Their impact on TLR signaling varies across specific contexts, diseases, and cell types [72,73,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138].
TLRs, essential for pattern recognition, detect diverse molecular signatures, whether located on cell membranes or within endosomes, initiating signaling pathways that culminate in the expression of cytokines, chemokines, and interferons (IFN) [139,140,141,142]. Within the CNS, microglia, neurons, astrocytes, and oligodendrocytes express various TLR subtypes, orchestrating intricate neuroimmune signaling [143,144,145,146,147]. Significantly, even in cases of mild neuropathological conditions, communication among neurons and glia is characterized by the upregulation of TLR ligands. This upregulation leads to the activation of inflammatory TLR signaling pathways, subsequently resulting in the overexpression of pro-inflammatory mediators [146,148]. Excessive TLR signaling has been implicated in various neuroinflammatory conditions, including depression, substance use disorders, TBI, neurodegenerative diseases, and epilepsy [64,74,76,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187]. These findings suggest potential therapeutic avenues for neurosteroids in mitigating neuroinflammation and neurodegenerative processes caused by TLR overactivation.
This review focuses on the role of endogenous neuroactive steroids in inflammation in both peripheral and brain contexts within neurological and psychiatric disorders. We delve into how these steroids, particularly pregnane neuroactive steroids, possess anti-inflammatory properties that operate independently of their effects on GABAA receptors. This suggests potential mitigation of excessive TLR signaling and the related inflammatory and neuroinflammatory conditions. Additionally, we review the involvement of androstane neuroactive steroids in the regulation of inflammation and neuroinflammatory processes. The complex interplay between these neuroactive steroids and immune responses underscores their therapeutic potential in addressing a broad spectrum of neurological conditions, particularly through modulation of TLR signaling pathways.

2. Neurosteroids and Neuroimmune Regulation

2.1. Neurosteroids: An Overview and Classification

Neuroactive steroids are a class of endogenous steroids synthesized de novo within the CNS, independently of the endocrine gland steroidogenesis [23,49]. In fact, the presence of the enzymes necessary for the in-situ synthesis of neurosteroids has been found in several brain regions [9,17,22,23,188,189,190,191]. In the brain, neurons are the primary producers of neurosteroids such as pregnenolone, progesterone, and allopregnanolone [14,15,16,17,18,19]. While the capacity for de novo neurosteroidogenesis has been demonstrated in primary glial cultures from rat brains and human microglial cell lines [20,192], research suggests that in the adult mouse brain, glial cells lack the capacity to produce neurosteroids. Studies have shown that the enzymes 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD), essential for the sequential synthesis of allopregnanolone and 3α,5α-THDOC from progesterone or deoxycorticosterone, respectively, are absent in glial cells. Specifically, there is no evidence of their presence in S100 calcium-binding protein B (S100β)- or glial fibrillary acidic protein (GFAP)-positive cells, indicating their absence in glial populations across various brain regions. Instead, these enzymes are predominantly localized in principal output neurons, including both glutamatergic and GABAergic neurons, distributed throughout diverse brain regions such as the cortex, hippocampus, olfactory bulb, thalamus, amygdala, striatum, and cerebellum [17]. These findings underscore the significance of both locally synthesized neurosteroids and those entering the brain from circulation in regulating brain function.
Neurosteroidogenesis begins with cholesterol or other steroidal precursors. The precursors are synthesized in the brain and systemically derived from steroids that cross the blood–brain barrier. A crucial step in steroidogenesis is the transportation of cholesterol within the mitochondria [193]. Here, cholesterol is converted to pregnenolone, the precursor of all steroids. Pregnenolone is then converted to progesterone, then other neurosteroids via progressive A-ring reductions [9,188]. Steroidogenesis involves several enzymes, protein transporters, redox partners, and cofactors. These mostly include forms of cytochrome P450 or hydroxysteroid dehydrogenases.
Based on their molecular structure, neuroactive steroids can be classified as follows:
  • Pregnane steroids, derived from progesterone, such as allopregnanolone, pregnanolone and 3α,5α-THDOC;
  • Androstane steroids, derived from DHEA and testosterone, such as ADIOL and androstanediol;
  • Sulfated steroids, such as pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS) (Figure 1).
Pregnane steroids are derived from progesterone, which originates from pregnenolone after its conversion from cholesterol by a dehydrogenase (Figure 1). Progesterone undergoes sequential A-ring reductions to yield allopregnanolone. This specific modification of the steroid structure significantly alters its biological activity by reducing the double bond in the A-ring, resulting in the formation of various pregnane derivatives. Additionally, another metabolite of progesterone, deoxycorticosterone, is reduced to form 3α,5α-THDOC. The biosynthesis of androstane steroids, primarily derived from DHEA and testosterone, involves similar A-ring reduction processes, producing products such as ADIOL, estradiol, and androstanediol (3α-diol) [194]. ADIOL, acting as an intermediate in the biosynthesis of testosterone from DHEA, requires the enzymatic activities of 17β-hydroxysteroid dehydrogenases (17β-HSD) [195]. It features a saturated A ring, an unsaturated bond in the B ring between C5 and C6, and a C19-methyl group [196]. Sulfated steroids are derived from the sulfation of specific precursors. For instance, pregnenolone sulfate is produced from the sulfation of pregnenolone [197]. Similarly, DHEA, a metabolite of 17OH-pregnanolone, is converted into DHEAS through sulfation [198,199].
The terminology for the neuroactive steroids was established in the late 1980s, during a period when the field was just beginning to unravel the direct influence of allopregnanolone on GABAA receptors [7,8,9]. Similarly, investigations unveiled the direct impact of pregnenolone on glutamate receptors [10]. Ongoing studies on neurosteroids such as allopregnanolone and pregnenolone have revealed a diverse array of action sites, suggesting that their multifaceted functions collectively contribute significantly to their neurological effects and potential to influence CNS disorders [11,12,13].
Many neurosteroids can exert their effects directly or through their metabolites, influencing various genomic and non-genomic mechanisms within the brain. For example, pregnenolone undergoes metabolic conversion to conventional steroids, such as progesterone, estrogen, androgen, glucocorticoid and mineralocorticoid, which are then mediated by their respective nuclear receptors [200,201]. Beyond its well-established role as a neurosteroid precursor, pregnenolone also has the capacity to directly interact with molecular targets. Notably, it can bind to microtubule-associated protein 2 (MAP2) and the cannabinoid receptor type 1 (CB1) [202,203]. In addition, estradiol and allopregnanolone can bind to and activate xenobiotic receptors, including the pregnane X receptor [204,205]. In the cytosol, estradiol binds to nuclear steroid receptors that are anchored to chaperone proteins. This binding releases the receptors from their anchoring, facilitating their dimerization [206]. Subsequently, the receptor complex migrates into the nucleus where, in conjunction with transcriptional coactivators, it binds to specific DNA sequences, thereby activating gene transcription [206]. This activation of genomic pathways by neurosteroids leads to trophic effects on neurons and glia, as well as modulation of neurotransmission and the synthesis of proteins that enhance neuroplasticity [207,208].
In contrast to the slow effects of steroid hormones via intracellular steroid receptors, neurosteroids can also rapidly modulate brain excitability through non-genomic actions on neurotransmitter receptors. GABAA receptors are the primary mediators of inhibitory transmission in the brain. These receptors are heteropentamers, typically composed of α, β, and either γ or δ subunits, forming chloride ion channels [209]. GABAA receptors facilitate two types of inhibitory neurotransmission: synaptic (phasic) and extrasynaptic (tonic) inhibition. Neurosteroids with GABAergic activity modulate both types, influencing phasic and tonic inhibition. These neurosteroids bind to specific sites on the GABAA receptors, located at the interface of the α and β subunits of synaptic receptors [210], distinct from the binding sites of GABA, benzodiazepines and barbiturates. Allopregnanolone and 3α,5α-THDOC are notably potent in most GABAA receptor subtypes [211], with enhanced potency at extrasynaptic receptors containing the δ subunit [32,212,213]. Exposure to neurosteroids prolongs the mean open time of the GABAA receptor chloride channels, increasing chloride current, leading to membrane hyperpolarization and a subsequent reduction in neuronal excitability. At high concentrations, neurosteroids like allopregnanolone can directly activate GABAA receptors even in the absence of GABA [214]. Neurosteroid modulation depends on specific structural features, including a 3α-hydroxy group on the A-ring and a hydrogen bond-accepting group on the D ring, found at either C20 or C17 of the steroid side chains [9,25,215]. Sulfated neurosteroids like PS and DHEAS act as weak non-competitive antagonists of GABAA receptors and potent allosteric modulators of N-methyl-D-aspartate (NMDA) receptors [216,217,218,219,220]. PS can also directly affect α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [221]. PS and DHEAS are sigma receptor agonists, whereas progesterone acts as a potent antagonist [222].
In summary, 3α-hydroxy-pregnane derivatives like allopregnanolone, pregnanolone, and 3α,5α-THDOC, along with various synthetic compounds, act as positive modulators of GABAA receptor subtypes [24,25,26,27,28,29,30]. These compounds enhance inhibitory neurotransmission mediated by GABAA receptors, leading to anxiolysis, sedation, anti-convulsant activity, anti-depressant activity, and the enhancement of inhibitory circuits in the brain [31,32,33,34,35,223]. Conversely, neurosteroids like PS and DHEAS are considered excitatory, known to enhance memory and produce anxiogenic effects [224]. The ability of neurosteroids to modulate excitatory and inhibitory circuits in the brain is essential for maintaining homeostasis and plays a role in neuropsychiatric diseases where this balance between excitation and inhibition is disrupted.
For many years, neurosteroids have been proposed as a therapy to restore altered GABAergic transmission in conditions such as depression, PTSD, PPD, anxiety, and substance use disorders [11,12,13,61,225,226]. These neuropsychiatric conditions share, among other features, a dysregulation in hypothalamic–pituitary–adrenal (HPA) axis activity [44,46,227,228,229,230,231,232,233], likely due to aberrant GABAergic signaling [234,235]. For example, patients with PTSD typically exhibit elevated levels of corticotropin-releasing factor (CRF) and a reduction in allopregnanolone levels in their cerebrospinal fluid (CSF) [236]. Animal models of affective disorders, such as social isolation in rats and mice, often display altered levels of HPA axis biomarkers and reduced levels of brain and plasma allopregnanolone [237,238,239,240,241]. Likewise, patients with AUD also exhibit elevated levels of CRF and cortisol along with blunted stress responses and reductions in serum allopregnanolone [47,228,242]. Similar results are found in animal models of ethanol dependence where CRF is elevated, various neurosteroids are depleted, and stress responses are blunted (see Morrow et al., 2020, for review [12]).
Although major depressive disorder (MDD) presents with various symptoms and affects multiple systems, dysregulation of HPA axis activity is a common feature [243]. Indeed, individuals with MDD frequently demonstrate low levels of allopregnanolone in both plasma and CSF [244,245,246]. Women experiencing PPD also show alterations in GABA and allopregnanolone levels [247,248] as well as HPA axis hypoactivity and hormonal imbalances [249,250]. Animal studies further support these findings, revealing that mice lacking the δ subunit in GABAA receptors exhibit behaviors akin to PPD, disinhibited CRF signaling, and elevated corticosterone levels during the postpartum period [251,252,253].
Over the past 30 years, evidence has emerged indicating that allopregnanolone and other neurosteroids can normalize dysfunction within the HPA axis. Administration of allopregnanolone has been shown to reduce stress-induced increases in CRF expression [254], while both allopregnanolone and 3α,5α-THDOC administration have prevented stress-induced elevations in adrenocorticotropic hormone and corticosterone levels when administered before stress induction in rats [255,256]. These findings suggest that treatment with allopregnanolone and other neurosteroids may hold therapeutic promise for neuropsychiatric disorders characterized by dysregulation in HPA axis and GABAergic signaling.
Most relevant to this review, neuropsychiatric diseases have been increasingly associated with neuroinflammation [257,258]. Recent research has uncovered the anti-inflammatory effects of neurosteroids in both the brain and peripheral tissues. Notably, these effects influence TLR activation and signaling, resulting in the inhibition of pro-inflammatory mediators and the enhancement of anti-inflammatory mediators. Importantly, these effects occur independently of neurosteroid actions on GABAA receptors [36,37,64,67,68,80].

2.2. Toll-like Receptor Signaling and Neuroimmune Regulation

TLRs, crucial for pattern recognition, detect various molecular signatures such as pathogen-associated molecular patterns, danger-associated molecular patterns, and microbiome/microbe-associated molecular patterns. These receptors are situated either on the cell membrane (e.g., TLR1, TLR2, TLR4, TLR5, TLR6, TLR11, TLR12) or within endosomes (e.g., TLR3, TLR7, TLR8, TLR9, TLR13). Once these molecular patterns are recognized, TLRs initiate signaling pathways that lead to the expression of cytokines, chemokines, and IFNs [139,140,141,142]. Typically, TLRs (excluding TLR3 and TLR4) signal primarily through myeloid differentiation primary response 88 (MyD88)-dependent pathways. However, TLR3 exclusively signals through toll/interleukin-1 receptor domain-containing adapter-inducing IFN-β (TRIF)-dependent pathways, while TLR4 can be activated through both MyD88- and TRIF-dependent pathways. The MyD88-dependent TLR4 pathway functions on the cell membrane and entails the recruitment of co-receptors: cluster of differentiation 14 protein (CD14), facilitating the recognition of lipopolysaccharide (LPS), and myeloid differentiation protein 2 (MD2), aiding in the recognition and binding of LPS. Additionally, adaptor molecules such as MyD88 and toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) are involved in this pathway [140,141]. Conversely, the TRIF-dependent TLR4 pathway occurs within endosomes and is initiated by adaptors TRIF and TLR4-specific TRIF-related adapter molecule (TRAM) [259,260,261]. TIRAP facilitates the transmission of signals from TLR4 to MyD88, while TRAM facilitates the transmission of signals from TLR4 to TRIF. Upon engagement of TLRs, the myddosome complex is formed, consisting of MyD88, interleukin-1 receptor-associated kinase (IRAK) 1, and IRAK4. Activation of IRAK1 triggers the activation of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) through lysine 63/K63 linked polyubiquitination on both TRAF6 itself and transforming growth factor beta-activated kinase 1 (TAK1). Activation of TAK1 subsequently leads to the activation of the inhibitor of kappa-B (IκB) kinase (IKK) complex, resulting in the phosphorylation and subsequent degradation of IκB proteins. This allows for the nuclear translocation of nuclear factor kappa-B (NF-κB) transcription factors and the initiation of gene transcription. Furthermore, activation of TAK1 leads to the activation of mitogen-activated protein kinases (MAPKs) (e.g., extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38), which in turn activate or phosphorylate various transcription factors, promoting the production of pro-inflammatory mediators [139,140,141,142,262].
In the CNS, various types of TLRs are present. Microglial cells express TLR1 through TLR9, neurons express TLR3, TLR4, TLR7, TLR8, and TLR9, astrocytes express TLR2, TLR3, and TLR9, while oligodendrocytes express TLR2 and TLR3 [143,144,145,146,147]. Interactions among microglia, neurons, astrocytes, and oligodendrocytes are pivotal in neuroimmune signaling, as highlighted by previous studies [146,263,264]. Microglia, the resident immune cells, respond to neuronal signals by engaging in immune responses, phagocytosis, and cytokine/chemokine secretion. Neurons contribute to maintaining microglial quiescence through regulatory signals [265,266]. Imbalances due to disease or injury trigger microglial activation, influencing tissue repair or neurotoxicity, which is modulated by various stimuli and the microenvironment [267]. Astrocytes release molecules affecting synaptic function and immune responses [268,269], while oligodendrocytes interact with microglia via immune receptor expression [270]. Additionally, cross-communication among brain cells involves the up-regulation of TLR ligands, activation of TLR signaling pathways, and subsequent over-expression of chemokines and cytokines, such as monocyte chemoattractant protein-1 (MCP-1), TNF-α, interleukin (IL)-1β, IL-6, high mobility group box 1 (HMGB1), and their receptors, which regulate distinct neuroimmune responses and cell-to-cell interactions [146,148].
Excessive inflammatory TLR activation is implicated in the development of various neuropsychiatric disorders. Activation of TLR pathways in glial cells, infiltrating lymphocytes, and neurons in the brain leads to the production of pro-inflammatory molecules, contributing to neuronal damage [169,173]. Stimulating the innate immune response with TLR4 agonist LPS in rodents results in neuronal injury, oligodendrocyte loss, hypomyelination, and periventricular cysts, reminiscent of periventricular leukomalacia and MS. Conversely, animals lacking functional TLR4 showed resistance to neurodegeneration [171,172]. Moreover, inhibition of the HMGB1/TLR4/MyD88 signaling pathway reduced levels of inflammatory cytokines and elevated brain-derived neurotrophic factor (BDNF) levels in the rat brain [174]. Additionally, neurodegeneration occurs due to the activation of the neuronal TLR7 pathway by the miRNA let-7 [170].
The activation of inflammatory responses through TLR signaling closely correlates with brain tissue damage and neurological impairment following TBI [167]. Inhibiting TLR4 resulted in enhanced neurological outcomes following TBI in mice, potentially attributable to heightened levels of anti-inflammatory monocytes and diminished IFN regulatory factor (IRF) 7 during acute inflammation, followed by a reduction in apoptosis and M2 microglial expression during chronic inflammation [168]. Moreover, the attenuation of TLR4/NF-kB inflammatory signaling after TBI in rats is associated with a notable reduction in neuronal cell apoptosis [166].
TLRs play a crucial role in modulating ischemic brain damage post-stroke [177,178]. In neonatal hypoxic-ischemic brain damage in rats, inhibition of the TLR4/MyD88 signaling pathway activation led to improved hippocampal structure and decreased inflammatory markers, indicating neuroprotective effects [179]. Additionally, TLR4-deficient mice exhibited reduced infarctions and a dampened inflammatory response following ischemic insult, underscoring the significance of TLR4 signaling in ischemic brain damage and inflammation [175].
TLR signaling emerges as a pivotal factor in epilepsy pathogenesis, evident from brain inflammation observed in both clinical cases and experimental models [185,186,187,271,272]. Of particular significance is the interaction between HMGB1 and TLR4 in this pathway, which plays a pivotal role in seizure generation and perpetuation. This signaling cascade triggers rapid alterations in NMDA receptors and induces long-term changes in seizure thresholds. Encouragingly, antagonists targeting the HMGB1/TLR4 pathway have shown promise in mitigating epilepsy-related pathology [186,271,273]. Furthermore, TLR3 deficiency has been shown to reduce spontaneous recurrent seizures, microglial activation, and levels of proinflammatory cytokines TNF-α and IFN-β following status epilepticus. Additionally, TLR3-deficient mice demonstrated enhanced survival rates post-status epilepticus [274].
The overactivation of TLRs significantly impacts the interplay of the innate immune system with neurotransmission, neuroendocrine functions, and stress-induced adaptations, thereby contributing to MDD and stress [152,153]. Among TLRs, TLR4 stands out for its prominent involvement in stress-induced neuroinflammatory responses and subsequent behavioral alterations. Moreover, the activation of the TLR4/MyD88/NF-κB pathway has been linked to chronic unpredictable mild stress in rat models [154,156]. In a mouse model of hippocampal neuroinflammation, the activation of the TLR4/TRAF6/NF-κB signaling pathway, triggered by LPS, emerges as a significant contributor to depressive-like behaviors [155]. Notably, recent research has unveiled a connection between LPS-induced TLR4 activation and depression in mice, particularly concerning deltamethrin-induced disruption of the gut–brain axis [151]. Additionally, inflammation resulting from the activation of both the TLR4 and TLR7 pathways has been observed in individuals experiencing PPD [64].
In the context of substance use disorders, TLRs are triggered and upregulated within the CNS in response to endogenous innate immune agonists like HMGB1 and miRNAs, due to exposure to substances such as alcohol and other addictive drugs. Specifically, in individuals with AUD, TLRs, particularly TLR2-9, and HMGB1 are induced, subsequently activating NF-κB. This activation leads to the upregulation of proinflammatory cytokines, chemokines, and their receptors. Ultimately, these molecular changes contribute to epigenetic modifications, neurodegeneration, and disruptions in synaptic plasticity, which play pivotal roles in the manifestation of cognitive and affective impairments observed in individuals with alcohol addiction [157,158,159,160,162,164,275].
Binge drinking, often intertwined with cognitive impulsivity, anxiety, and smoking habits, triggers neuroimmune signaling through TLR4. In the brain, this pathway’s activation is facilitated by the GABAA α2 subunit protein, when it operates independently, separate from the GABAA receptor. Consequently, it initiates cyclic adenosine monophosphate response element-binding protein (CREB) activation and the upregulation of CRF, tyrosine hydroxylase (TH), and MCP-1. Encouragingly, gene therapy aimed at modulating neuronal TLR4, α2, or MCP-1 has shown promise in mitigating binge drinking, nicotine sensitization, and cognitive impulsivity, highlighting their potential as key regulators of these behaviors [147,148,161,163,165].
Interestingly, TLRs are implicated in the immunopathogenesis of schizophrenia. Drug-naïve patients with schizophrenia exhibited increased TLR4 mRNA levels and unaltered TLR3 mRNA levels in peripheral blood mononuclear cells (PBMC), alongside elevated TLR4 and TLR8 mRNA levels and reduced TLR3 mRNA levels in white blood cells compared to healthy controls [180,181]. Additionally, the correlation between TLRs and complement factors suggests a coordinated immune response in schizophrenia. Higher TLR8 mRNA levels were inversely associated with cortical thickness of the cingulate gyrus, hinting at a potential link between TLR activation and structural brain changes in schizophrenia [181]. Furthermore, no significant changes in TLR3 and TLR4 gene expression in PBMCs were observed after three months of antipsychotic medication [180].
TLRs emerge as pivotal contributors to neuropathic pain [182,183]. Studies revealing a causal relationship demonstrate a significant association between TLR4 and neuropathic pain. Mouse models lacking functional TLR4 following L5 nerve transection exhibit reduced behavioral hypersensitivity, alongside diminished expression of spinal microglial markers and proinflammatory cytokines. Similarly, rats with downregulated TLR4 post L5 nerve transection display comparable results [276]. Furthermore, CD14’s significant involvement in the LPS-TLR4 signaling pathway in nerve injury-induced neuropathic pain is underscored, as evidenced by decreased behavioral sensitivity in CD14 knockout mice following L5 spinal nerve transection [277]. Moreover, heightened TLR3 expression emerges as a crucial factor in neuropathic pain onset in rats subjected to the L5 spinal nerve ligation model. This increased TLR3 activity influences autophagy pathways within affected neurons, contributing to neuropathic pain development [278]. Similarly, augmented TLR7 expression in dorsal root ganglion neurons exacerbates neuropathic pain, while inhibiting this upregulation alleviates pain hypersensitivity and reduces inflammatory markers in the dorsal horn. Conversely, TLR7 overexpression induces pain sensitivity [279]. Additionally, activation of TLR8 in dorsal root ganglion neurons fosters ERK activation, prompting the production of inflammatory mediators and heightened neuronal hyperexcitability, thereby contributing to neuropathic pain post spinal nerve ligation [280]. Notably, blocking the TLR2/MyD88/NF-κB pathway in microglia within the spinal cord dorsal horn confers neuroprotection, offering sustained relief from neuropathic pain through the secretion of tumor necrosis factor-stimulated gene 6 protein [281].
Although TLRs are commonly linked to inflammation, evidence suggests they can exhibit both pro-inflammatory and anti-inflammatory functions, influenced by factors such as cell type, sex, subcellular compartmentalization of TLR signaling, ligand type, and involvement of co-receptors [80,282,283,284]. For instance, TLR2 demonstrates anti-inflammatory properties when exposed to polysaccharide A from Bacteroides fragilis, triggering IL-10 and IFN-γ secretion, which are protective against viral encephalitis [285,286,287]. Additionally, TLR2 plays a vital role in the anti-inflammatory response to Listeria monocytogenes infection, with endosomal TLRs predominantly responsible for immune suppression against phagosome-confined bacteria [288]. In glucocorticoid treatment and the resolution phase of inflammation, TLR2 upregulation occurs, facilitated by glucocorticoid receptor-dependent mechanisms. This upregulation leads to the production of soluble TLR2, known to antagonize TLR2-dependent actions, and its presence in extracellular vesicles acts as decoy receptors, dampening inflammatory responses [289]. On the other hand, TLR4’s anti-inflammatory effects rely on its intracellular compartmentalization, orchestrated by the p110δ isoform of phosphoinositide 3-kinase (PI3K). This process guides TLR4 from an initial plasma membrane complex associated with TIRAP-MyD88 to a later endosomal complex involving TRAM-TRIF, triggering the production of anti-inflammatory type I IFNs and IL-10 [80,283,284]. Mechanistically, p110δ reduces the abundance of the TIRAP-anchoring lipid phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P2) on the plasma membrane. This action prompts the endocytosis of CD14-TLR4 by mobilizing Ca2+. The subsequent turnover of PtdIns(4,5)P2 frees TIRAP into the cytoplasm, where it undergoes degradation by calpains and the proteasome. Disabling p110δ shifts the balance toward proinflammatory early signaling, heightening sensitivity to endotoxins [283,284]. Moreover, in male alcohol-preferring rat brains, neurosteroid allopregnanolone enhances the activation of the endosomal anti-inflammatory TLR4/TRIF pathway, while inhibiting it in females, suggesting a sex-dependent mechanism [80]. Additionally, TLR4 recognizes specific molecules from probiotics, like exopolysaccharide (EPS) from Bacillus subtilis, to address intestinal inflammatory diseases. EPS activates the anti-inflammatory TLR4 pathway, leading to the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in dendritic cells, inhibiting T cell proliferation via the kynurenine/aryl hydrocarbon receptor circuit. Notably, unlike LPS, EPS administration does not induce the release of inflammatory cytokines, emphasizing the distinct effects of different TLR4 agonists [290]. Lastly, TLR9 signaling regulates anti-inflammatory responses in lupus independently of MyD88, while TLR10 upregulation by vitamin D promotes the expression of anti-inflammatory cytokines in microglial cells, favoring M2 polarization [291,292,293].
In summary, TLRs play a crucial role in recognizing various molecular patterns, triggering signaling pathways that lead to the expression of cytokines, chemokines and IFNs. Overactive TLRs have been associated with various neurological disorders, encompassing neurodegeneration, AUD, TBI, epilepsy, and psychiatric diseases. This emphasizes the importance of therapeutic approaches targeting TLR signaling, with an emphasis on inhibiting inflammatory pathways while enhancing anti-inflammatory mechanisms. Such interventions offer potential for safeguarding neurological health and managing neuroinflammatory disorders.

2.3. Mechanisms of Action of Pregnane Neuroactive Steroids on Toll-like Receptors

Pregnane neuroactive steroids demonstrate anti-inflammatory effects in both the brain and peripheral tissues. These effects impact TLR activation and signaling pathways, leading to the inhibition of pro-inflammatory mediators and the enhancement of anti-inflammatory mediators [36,37,64,67,68,69,71,80,294].
Allopregnanolone reduces pro-inflammatory TLR signal activation through a highly specific mechanism (Figure 2). This mechanism involves the inhibition of crucial protein–protein interactions essential for TLR activation. Its role as an inhibitor is particularly pronounced in the activated TLR signaling pathways, while it leaves the steady-state, non-activated pathways unaffected. Allopregnanolone’s inhibitory action has been delineated in pro-inflammatory signaling triggered by TLR2, TLR4, and TLR7. This inhibition hinges on its ability to disrupt key protein binding steps, including those between TLR2 and MyD88, TLR4 and MD2, TLR4 and MyD88, and TLR7 and MyD88. These inhibitions have been observed both in the mouse macrophage RAW264.7 cell line and in rat brains [36,67].
Intriguingly, allopregnanolone also inhibits the binding of the GABAA α2 subunit protein to TLR4 in the rat brain [36]. This is of significance as previous research has indicated that the α2 subunit protein binding to TLR4 is the essential binding step for TLR4 signal activation in the alcohol preferring (P) rat brain [147,161].
The disruption of these protein–protein interactions and allopregnanolone’s intervention leads to a substantial reduction in the activation of various downstream components within the TLR signaling pathways. These inhibitory effects encompass decreased levels of TRAF6, as well as reduced phosphorylation (p) or activation of TAK1 and ERK1/2. Additionally, transcription factors such as NF-κB, CREB, activating transcription factor (ATF)2, signal transducer and activator of transcription (STAT)1, and IRF7 exhibit diminished activity. Ultimately, this cascade of events results in decreased expression of pro-inflammatory factors, including MCP-1, HMGB1, TNF-α, IL-1β, and IL-6 (Figure 2) [36,37,67].
Importantly, allopregnanolone inhibition of TLRs specifically targets the MyD88-dependent pro-inflammatory pathways, leaving the TRIF-dependent TLR3 pathway unaffected [67]. Furthermore, these inhibitory effects are independent of GABAA receptor activity and are replicated by pregnenolone, which lacks GABAergic activity. In addition, the GABAergic steroid 3α,5α-THDOC lacks many of the anti-inflammatory actions of allopregnanolone, although it does exhibit some influence on downstream TLR4 and TLR7 pathway members in cultured human monocyte-derived macrophages obtained from female, but not male donors [36,37].
In human macrophages, allopregnanolone consistently demonstrates its ability to inhibit TLR4 activation and the associated inflammatory pathway members CREB, STAT1, MCP-1 and TNF-α in cells from both male and female subjects. However, the inhibition of TLR7 activation appears to be sex-specific, primarily blocking STAT1, IRF7, IL-1β, and IL-6 elevations in macrophages from female donors. This finding suggests potential sex differences in the actions of pregnane neuroactive steroids on TLR7 receptors, warranting further investigation in future studies.
Furthermore, other studies show that allopregnanolone inhibits the activation of TLR4 and TLR2 in both mouse macrophages and microglial cells by inducing the degradation of both TLR2 and TIRAP, leading to reduced TNF and IL-6 levels [68]. Notably, a similar impact of allopregnanolone on TIRAP degradation was observed in P rat brains [80].
Additionally, allopregnanolone plays a crucial role in modulating the immune response by inducing anti-inflammatory signaling through the endosomal TRIF-dependent TLR4 pathway, but notably, this effect is observed in the male rat brain and not in the female rat brain (Figure 3) [80]. This process culminates in the elevation of IL-10, a central regulator of inflammation in both brain and peripheral tissues [295,296,297,298]. The underlying mechanism hinges on several crucial steps. Allopregnanolone triggers the translocation of TLR4 from the plasma membrane to endosomes, driven by the upregulation of the p110δ isoform of PI3K and the degradation of TIRAP. This results in the accumulation of TLR4 and TRIF, leading to the formation of a TLR4-TRIF complex within endosomes, subsequently activating the anti-inflammatory signaling cascade [80,283,284]. Allopregnanolone further enhances this pathway by increasing phosphorylated (activated) TRAM levels, resulting in the upregulation of transcription factor specificity protein 1 (SP1) and subsequent production of IL-10 [80]. Additionally, allopregnanolone upregulates BDNF levels, potentially amplifying IL-10 production, and release [77,79,80,299,300,301]. Furthermore, allopregnanolone stimulates the accumulation of endosomal Ras-related protein Rab7, which holds the potential to influence the equilibrium between pro-inflammatory and anti-inflammatory TLR4 signaling pathways within the male rat brain [80]. The mechanism underlying the sex-specific effects of allopregnanolone on IL-10 remains unclear and might potentially be influenced by varying sensitivities to allopregnanolone doses.
Interestingly, allopregnanolone, along with 3α,5α-THDOC and pregnenolone, can enhance the expression of the anti-inflammatory chemokine fractalkine (CX3CL1) within the alcohol-preferring P rat brain [302]. This is noteworthy, especially considering that fractalkine is innately downregulated in these rats. The downregulation of fractalkine can be attributed to inflammatory TLR4 signaling, which results in the dysregulation of anti-inflammatory modulators like fractalkine in favor of inflammatory modulators like MCP-1. The data suggest that allopregnanolone may contribute to maintaining a homeostatic balance between inflammatory and anti-inflammatory modulators within the brain, potentially influencing susceptibility to inflammatory brain diseases, including neuropsychiatric conditions [146,302].
Like allopregnanolone, pregnenolone, which lacks innate GABAergic properties, plays a role in reducing pro-inflammatory TLR signal activation by inhibiting the binding of TLR4 with MD2 and TLR4 with MyD88. This indicates that pregnane neuroactive steroids’ inhibitory effects on pro-inflammatory TLR signaling are not dependent on GABAergic mechanisms [36]. Furthermore, while pregnenolone serves as a precursor for allopregnanolone in steroidogenic cells, the observed inhibitory effects of pregnenolone in the mouse macrophage RAW264.7 cell line were not attributed to its conversion to allopregnanolone. This conclusion is supported by the detection of minimal conversion (less than 0.1%) in these cells [36].
High-throughput mass spectrometry identified 11 specific pregnenolone-binding proteins in Th2 CD4+ immune cells and 25 in CD8+ immune cells, located in mitochondria and the endoplasmic reticulum, with a significant presence in membranes, highlighting pregnenolone’s non-genomic activity [303,304]. Pregnenolone possesses the capability to directly interact with MAP2 and CB1 receptors in the brain [202,203]. Furthermore, it appears to attenuate inflammatory TLR signaling by modulating CB1 receptors, potentially contributing to anti-inflammatory effects [305,306]. However, future research is needed to elucidate whether pregnenolone directly binds to components of TLR signaling pathways and TLRs themselves, and if it indeed suppresses inflammatory TLR signaling via CB1 receptors.
Furthermore, pregnenolone exhibits another facet of its anti-inflammatory action by promoting the ubiquitination and degradation of TLR2 and TIRAP [68]. In the RAW264.7 cells, pregnenolone selectively inhibits the formation of the TLR4/MD2 complex, a pivotal step in initiating the TLR4-mediated signaling pathway. This inhibition results in a significant reduction in the activation of various downstream components within the TLR4 signaling pathway when the cells are exposed to agonists such as LPS. These inhibitory effects involve a decrease in TRAF6 levels and a reduction in the activities of TAK1, NF-κB, and CREB. Consequently, there is a decreased expression of pro-inflammatory mediators, including MCP-1, HMGB1, and TNF-α. Importantly, this inhibition by pregnenolone is specific to the LPS-activated TLR4 pathways and does not affect these proteins in non-activated cells [36].
Furthermore, in experiments involving mouse and human macrophage cell lines, along with mouse microglial cells, pregnenolone demonstrates its ability to suppress the secretion of pro-inflammatory cytokines, particularly TNF-α and IL-6, in response to TLR4 and TLR2 signal activation. Pregnenolone achieves this by promoting the ubiquitination and subsequent degradation of TIRAP and TLR2. Additionally, pregnenolone triggers the activation of the microtubule plus end-binding protein, further enhancing the degradation of TIRAP and the suppression of TLR4, thus reinforcing its neuroprotective mechanism. Crucially, while pregnenolone effectively down-regulates pro-inflammatory responses dependent on MyD88, it does not appear to influence the MyD88-independent pathway of TLR4 signaling. This is evident from unaltered levels of LPS-induced IFN-β secretion in RAW264.7 cells [68].
Progesterone reduces pro-inflammatory TLR activation by decreasing the phosphorylation of the IκBα, thereby enhancing its expression. This leads to diminished phosphorylation of NF-κB and inhibits its expression and nuclear translocation. Progesterone also downregulates TLRs, MyD88 and CD14 levels and concomitant inflammatory cytokines while upregulating anti-inflammatory proteins such as suppressor of cytokine signaling (SOCS) 1 [69,71,72,73,294,307,308,309]. Furthermore, its structural similarities with pregnenolone and allopregnanolone suggest it may share the same abilities to inhibit TLR activation described above. Moreover, progesterone modulates the production of nitric oxide (NO) and IL-12 in macrophages through both glucocorticoid receptor-mediated and progesterone receptor-mediated mechanisms following TLR4 signal activation [70]. In the context of TBI, progesterone dampens the activation of TLR2 and TLR4 signaling pathways. This reduction in TLR2 and TLR4 levels, coupled with decreased NF-κB binding activity, leads to the suppression of inflammatory cytokine production, specifically IL-1β, TNF-α, and IL-6, in the pericontusional cortical region [74]. Furthermore, in BV-2 microglia, progesterone suppresses TLR4 activation induced by LPS and reduces the expression of proinflammatory mediators, including TNF-α, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as the reduction of NO release [294,310]. In macrophages, progesterone decreases IL-6 and NO production following TLR4 and TLR9 signal activation [69] and suppresses the secretion of TNF-α and IL-6 in response to TLR4 and TLR2 signal activation [68]. It also inhibits LPS-induced iNOS expression, TLR4 expression, and NF-κB activation. Additionally, progesterone up-regulates the expression of SOCS1 protein as a negative feedback regulator [69]. Prior treatment of cells with progesterone as well as estradiol inhibits the activation of TLR2 and TLR4 pathways induced by TLR2 agonist Pam3CSK4 and TLR4 agonist LPS, resulting in reduced TNF and IL-6 levels in human cord blood mononuclear cells in newborns [309]. Moreover, progesterone and estradiol downregulate TLR2, CD14, and COX2, inhibit NF-κB signaling, and reduce prostaglandin E2 secretion in LPS-activated primary human monocytes, independently of MAPK pathway [308]. In cases of pre-eclampsia, progesterone inhibits TLR4 activation in human PBMCs. Increasing progesterone concentration correlates with reduced mRNA levels of TLR4, MyD88, and NF-κB, while elevating IκBα protein levels. Furthermore, progesterone reduces the expression of TNF-α and IL-6, underscoring its potential to modulate the immune response in this condition [71].

2.4. Mechanisms of Action of Androstane Neuroactive Steroids on Toll-like Receptors

Androstane neuroactive steroids like estrogens, androgens, DHEA, and ADIOL have complex effects on TLR expression and activation. These effects are notably context-dependent, influenced by specific diseases, and vary across different cell types [137].
ADIOL, also known as androstenediol or 5-androstenediol, holds promise as a potent anti-inflammatory agent, particularly within the brain where it can mitigate inflammatory responses triggered by TLR activation. ADIOL is synthesized from its precursor, DHEA, within microglia by reducing the 17-keto group [195]. It serves as a selective modulator of estrogen receptors (ER), effectively suppressing inflammatory reactions in microglia and astrocytes [108]. Studies by Salama et al. revealed that ADIOL reduces NF-kB levels in both the striatal and nigral regions of a rat model with rotenone-induced Parkinson’s disease (PD) [311]. Additionally, ADIOL promotes the production of the anti-inflammatory cytokines IL-4 and IFN-γ in experimental autoimmune encephalomyelitis, mitigating axonal damage resulting from demyelination by shifting microglial polarization toward a reparative state [312,313]. ADIOL also exhibits inhibitory effects on the expression of IL-1β when human microglia are stimulated with the TLR4 agonist LPS [314], underscoring its role in countering inflammation following TLR4 signal activation. Hanna et al.’s research further supports ADIOL’s anti-inflammatory potential by demonstrating reduced levels of TNF-α and IL-6 in the striatal area when administered before exposure to 3-nitropropionic acid-induced neurotoxicity [315]. Moreover, ADIOL has demonstrated the ability to suppress pro-inflammatory cytokines, including TNF-a, in murine models of carrageenan-induced pleurisy and septic shock resulting from LPS-induced TLR4 activation. It achieves this through its binding and transactivation of sex steroid receptors, with a preference for ERβ over ERα and androgen receptors (AR) [316]. ADIOL also effectively inhibits the TLR4 inflammatory pathway, reducing TLR4, NF-kB, and HMGB1 levels in peritoneal tissues [106].
Estrogens and androgens can display both anti-inflammatory and pro-inflammatory effects on TLRs, depending on the context. Estrogen-activated ERα in the brain reduces inflammatory mediator production and suppresses microglial activation via cytoplasmic PI3K induction. This activity inhibits the intracellular transport of NF-kB, which is initiated by the activation of TLR4 signaling through LPS stimulation [116,117,317]. Estradiol shortens the pro-inflammatory phase induced by LPS in mouse macrophage RAW 264.7 cells by activating intracellular ER. Estradiol, by modulating the SOCS3 and STAT3 signaling pathways, directs the inflammatory process towards the “acquired deactivation” phenotype. This phenotype, dependent on IL-10, is instrumental in tissue remodeling and the restoration of homeostasis [122]. However, estradiol, administered chronically, enhances peritoneal macrophage activation via ERα. This is achieved by downregulating the PI3K/protein kinase B (Akt) pathway, which, in turn, relieves its inhibitory effect on TLR4 signaling. Consequently, peritoneal macrophages become more responsive to TLR4 activation, resulting in increased proinflammatory cytokine production and iNOS expression [132,133].
Estradiol and progesterone had no significant effect on the expression of TLRs in human fallopian tube epithelial cells when administered separately. However, the co-administration of these neuroactive steroids led to significant changes in TLR expression [72]. Estradiol and progesterone both inhibit TLR3 signal activation and IL-6 production in these cells [131]. In the context of bone metabolism, estrogen downregulates the IL-6 gene by inhibiting NF-kB and potentially influencing CCAAT enhancer binding protein beta, even without a functional ER binding site [128].
The interaction among estradiol, TLR5, and the immune response in the bladder is intricate. Estradiol and progesterone both contribute to a reduction in TLR5 expression and impact its functional activity in the bladder, which is evident in the levels of IL-6 produced in response to flagellin. Notably, there is an inverse relationship between TLR5 expression and IL-6 production. Estradiol enhances IL-6 production, whereas progesterone intensifies it even further when compared to hormone-free or combined estrogen-progesterone environments [73]. Estradiol can also enhance TLR8 expression in human PBMCs. This process is ERα-dependent, involving direct DNA binding of ERα to an estrogen response element located downstream of the TLR8 gene [130].
In vitro, testosterone reduces TLR4 expression and sensitivity to TLR4-specific triggers in mouse macrophages. In vivo, the removal of endogenous testosterone increases susceptibility to endotoxic shock and elevates TLR4 expression in isolated mouse macrophages, suggesting a link between testosterone’s immunosuppressive effects and TLR4 regulation [135]. In contrast, dihydrotestosterone (DHT) increases TLR4 expression, while LPS boosts AR expression, promoting hepatocellular carcinoma progression and migration [318]. Additionally, testosterone persistently dysregulates hepatic expression of TLR6 and TLR8 induced by Plasmodium chabaudi malaria through epigenetics, while DHT modulates TLR7 and inhibits TLR9 expression by preventing cell apoptosis of plasmacytoid dendritic cells [136,319].
In BV-2 microglia, DHEA demonstrates effective inhibition of nitrite production induced by LPS-stimulated TLR4 activation, achieving this through a dose-dependent reduction in iNOS mRNA and protein levels, without necessitating new protein synthesis or mRNA destabilization. This highlights DHEA’s potent regulatory influence on microglial immune responses [320]. Similarly, in macrophage RAW 264.7 cells, DHEA attenuates inflammatory responses triggered by LPS-induced TLR4 activation. This suppression is accomplished by inhibiting Akt, MAPK, and the downstream NF-κB pathway while concurrently promoting the activation of autophagy-related nuclear factor erythroid 2–related factor 2 [112]. Furthermore, DHEA exhibits the potential to enhance neutrophil phagocytosis, reduce reactive oxygen species production, and decrease IL-8 release by modulating NF-κB signaling [134]. However, in a pig model of trauma and delayed sepsis, LPS-induced TLR4 signaling leads to a significant reduction in endogenous DHEA levels. Despite the administration of exogenous DHEA effectively elevating DHEA levels in treated animals, it fails to mitigate the subsequent systemic inflammatory response and organ dysfunction triggered by TLR4 activation, ultimately resulting in septic symptoms and pulmonary failure [321]. Moreover, DHEA administration in mice following sepsis induction resulted in the restoration of TLR expression, particularly TLR2 and TLR4 mRNA, in splenic macrophages. This reversal of TLR down-regulation is associated with a reduction in anti-inflammatory IL-10 responses and an increase in proinflammatory TNF-α production [138]. In summary, DHEA shows promise in modulating immune responses via TLR activation in microglial and macrophage cell lines. However, its effectiveness in an animal trauma and sepsis model is limited, and its impact on TLR expression presents complex outcomes. Additional research is required to gain a comprehensive understanding of DHEA’s role in immune modulation.
The interactions between androstane neuroactive steroids and TLRs reveal a complex scenario of immune regulation with implications for various physiological and pathological processes. Further research in this field holds promise for understanding and using these interactions for therapeutic purposes, particularly in the context of neuropsychiatric disorders.

3. Benefits of Neurosteroid-Mediated Neuroimmune Modulation in Neuropsychiatric Disorders

3.1. Depression

The association between depression and immune responses has been extensively documented in numerous studies, underscoring the pivotal role of inflammatory TLR signaling [152,153,257,322,323,324,325,326,327]. Proinflammatory cytokines and chemokines resulting from TLR activation are now recognized as potential biomarkers for depression [152,328], PPD [64,329,330], and PTSD [331,332,333].
In MDD, patients often exhibit elevated levels of TNF-α and IL-6, along with upregulated MyD88 and TRIF components [323,324,334]. TLR4 expression correlates with MDD symptoms, anxiety, and weight loss, and postmortem studies on MDD suicides reveal elevated TLR4 levels in the brain and blood mononuclear cells [335,336,337,338].
In the etiology of PPD, inflammation plays a significant role, with TLR4 and TLR7 pathway activation leading to increased pro-inflammatory markers such as TNF-α and IL-6 [64,258,339]. IL-6, IL-1β and TNF-α levels correlate positively with depressive scores in women with PPD, and elevated IL-1β concentrations are found in the CSF of patients developing persistent pain and/or PPD after cesarean delivery [64,340,341]. Elevated levels of IL-6 and TNF-α at delivery are associated with postpartum depressed mood, and increased IL-6 and its receptor levels are observed in women with PPD [342,343]. Additionally, mothers who deliver prematurely show increased IL-6 and IL-8 levels [344].
PTSD involves dysregulated HPA axis activity, resulting in elevated glucocorticoid levels and activation of microglia [345,346]. Glucocorticoid upregulation activates the inflammatory TLR2 pathway [347] and promotes the release of IL-1β, IL-6, and TNF-α from microglia [348,349,350,351]. Additionally, elevated glucocorticoids activate astrocytes, leading to excessive IL-1 release and disruption of glutamate homeostasis, potentially causing cellular degeneration [352]. Animal models and clinical studies have shown an association between elevated glutamate levels in the CSF and PTSD [353,354,355].
Preclinical research has shown that pregnenolone and/or allopregnanolone levels are reduced in animal models of stress, depression, and PTSD [39,40]. Furthermore, clinical investigations have confirmed these findings among individuals with depression [43,44,45] and those with a history of depression [46]. Given the limitations observed with these steroids, researchers have explored the potential therapeutic effects of neurosteroid administration. Allopregnanolone and its precursor molecules, such as pregnenolone/progesterone, have shown promising therapeutic efficacy in animal models exhibiting depression-like behavior induced by chronic stress [356]. Clinical studies consistently demonstrate the remarkable effectiveness of allopregnanolone in treating PPD [62,63,64,65,76,357,358].
In our recent study involving patients treated with brexanolone (a commercial formulation of allopregnanolone) for PPD, the therapeutic effects were associated with the inhibition of inflammatory mediator production and suppression of inflammatory responses to TLR4 and TLR7 pathway activators [64]. Brexanolone reduced baseline levels of the inflammatory markers TNF-α and IL-6, and these effects predicted improvement in the Hamilton Rating Scale for Depression (HAM-D) scores. Additionally, brexanolone treatment inhibited the blood cell response to the inflammatory immune activators LPS and imiquimod, suggesting its blockade of TLR4 and TLR7 pathways, activated by LPS and imiquimod, respectively. These responses also predicted improvement in HAM-D scores in the patients, representing a significant advancement in our understanding of brexanolone’s effectiveness and suggesting that inflammatory signaling may contribute to the etiology of PPD. This finding marks the first clinical correlation between allopregnanolone’s inhibition of inflammatory signaling and its clinical efficacy. Ongoing studies by our group and others are exploring the therapeutic potential of neuroactive steroids in various disorders, including depression. The emerging evidence underscores the significance of inhibiting neuroimmune signaling in their mechanisms of action against inflammatory conditions.
Moreover, in a double-blind phase 3 randomized clinical trial, zuranolone, also known as SAGE-217 (an allopregnanolone derivative), showed significant improvements in depressive symptoms, as measured by the HAM-D score, among women with PPD. Sustained differences favoring zuranolone were noted from day 3 to day 45, accompanied by positive outcomes in response and remission rates, along with improvements in anxiety symptoms [359]. Additionally, in a double-blind phase 2 trial, administration of zuranolone daily for 14 days to patients with MDD resulted in a reduction in depressive symptoms on day 15. Adverse events were more common in the zuranolone group than in the placebo group. Further trials are needed to determine the durability and safety of zuranolone in MDD and to compare zuranolone with available treatments [360].
However, the study investigating ganaxolone, another synthetic derivative of allopregnanolone, for the treatment of PTSD did not demonstrate significant differences between ganaxolone and placebo in improving PTSD symptoms. However, challenges with dosing and pharmacokinetics may have contributed to these findings. Future research on ganaxolone should consider higher dosing, rigorous dosing adherence monitoring, longer placebo-controlled testing, and targeting treatment to specific PTSD subpopulations with dysregulated neuroactive steroid levels [361].
Pregnenolone, as an add-on therapy, shows promise in alleviating depressive symptoms in adults with bipolar disorder (BPD), highlighting its potential as a safe and effective treatment option for BPD-associated depression [43]. Testosterone, as observed in randomized placebo-controlled clinical trials, is associated with a significant reduction in depressive symptoms among men, demonstrating both effectiveness and efficacy [362].
Interestingly, the competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor, trilostane, modulates the levels of neuroactive steroids in both peripheral and brain regions. Notably, trilostane demonstrates facilitative effects on the antidepressant activity of DHEAS [363,364].
In summary, neurosteroid-mediated neuroimmune modulation presents a promising avenue for treating neuropsychiatric disorders like depression. Studies highlight the role of inflammatory signaling in these conditions, with drugs like brexanolone showing effectiveness in alleviating symptoms, particularly in PPD. While challenges persist, ongoing research underscores the potential of neuroactive steroids to offer novel therapeutic options for these conditions, complementing existing treatment strategies.

3.2. Substance Use Disorders

The influence of alcohol and psychoactive drugs such as cocaine, methamphetamine, cannabis, and nicotine on neuroinflammation and immune responses is a growing area of research in both clinical and preclinical fields. Understanding their impact on inflammatory pathways and neuroimmune function is pivotal for unraveling their neurobiological mechanisms and identifying potential therapeutic interventions, including the promising utilization of neurosteroids.
Elevated levels of MCP-1 have consistently been observed in various brain regions, including the ventral tegmental area, substantia nigra, hippocampus, and amygdala, among individuals with AUD [365], with similar findings in mouse brains [366]. Moreover, alcohol exposure triggers the release of pro-inflammatory cytokines and activates chemokine/cytokine receptors in glial cells, such as astrocytes and microglia [266,367,368,369].
Excessive neuroinflammation associated with alcohol addiction is often attributed to the activation of inflammatory TLR pathways. Recent research highlights the involvement of the HMGB1–TLR–MyD88–NF-κB signaling pathway in contributing to neurodegeneration observed in the orbitofrontal cortex of postmortem human subjects with AUD [160]. Chronic and acute alcohol exposure activates various TLR-mediated pathways, leading to microglia activation and elevated levels of pro-inflammatory cytokines and chemokines in the brain [147,158,159,370,371,372,373,374,375,376,377,378]. Alcohol also disrupts the homeostatic balance of pro-inflammatory and anti-inflammatory factors in the brain, favoring pro-inflammatory factors [146].
Chronic cocaine use has been associated with increased levels of IL-6 and decreased levels of IL-10, as well as an imbalance in pro-inflammatory and anti-inflammatory markers. Additionally, cocaine exposure influences glutamate release and transporters, contributing to neuroinflammation and microglial activation [58,379,380,381].
Methamphetamine exposure exacerbates oxidative stress, apoptosis, and neuroinflammation, characterized by microglial activation and the release of inflammatory cytokines. Methamphetamine-induced dopamine and glutamate release further exacerbate neuroinflammation [382,383,384,385,386,387].
Cannabis exposure exhibits immunomodulatory effects, but some data suggest a pro-inflammatory impact, particularly in individuals with cannabis use disorders [305,388,389,390].
Nicotine’s effects on the immune system are complex and vary depending on exposure and context, with evidence suggesting both pro-inflammatory and anti-inflammatory effects [147,391,392,393,394].
These dysregulations in neuroimmune and immune signaling induced by substance abuse can compromise neural functions, lead to neurodegeneration, and increase neurotoxicity, all contributing to the behavioral manifestations associated with substance use disorders.
Preclinical and clinical investigations underscore the beneficial impact of neuroactive steroid treatment on substance abuse outcomes. Milivojevic et al. (2023) [61] found that pregnenolone treatment in individuals with AUD significantly reduces stress and alcohol cue-induced craving, while also alleviating stress-induced anxiety and normalizing HPA axis and autonomic responses. Additionally, studies in alcohol-preferring P rats by O’Dell et al. (2005) [395] and Besheer et al. (2010) [48] demonstrate that systemic administration of pregnenolone, epiallopregnanolone (3β,5β-THP), or the synthetic neurosteroid 3α,5β-20-oxo-pregnane-3-carboxylic acid (3α,5β-PC) reduces ethanol self-administration. Furthermore, Ornelas et al. (2023) [50] found that infusion of allopregnanolone in the nucleus accumbens decreases alcohol self-administration in female P rats.
It should be noted that P rats represent a model of innate TLR activation where the effects on brain TLR pathways can be examined in the absence of peripheral immune activation. Overactivation of inflammatory TLR signaling pathways leads to an imbalance in pro-inflammatory and anti-inflammatory factors favoring the former [146]. Allopregnanolone treatment of P rats inhibits inflammatory MyD88-dependent TLR4 and TLR7 signaling, resulting in reduced MCP-1 levels in the brain. Additionally, allopregnanolone enhances anti-inflammatory TRIF-dependent TLR4 signaling, leading to increased IL-10 levels in the brain [36,67,80].
In individuals with cocaine use disorder (CUD), after progesterone treatment, both men and women experienced reduced cue-induced cocaine craving and cortisol responses, along with improved inhibitory control performance. However, women reported lower negative emotions and higher relaxed mood ratings after stress exposure, unlike men [58]. Additionally, administering progesterone to individuals with CUD leads to heightened levels of GABAergic neurosteroids, namely allopregnanolone and pregnanolone, both in men and women. Notably, high allopregnanolone levels were associated with normalized cortisol responses to stress, improved mood, enhanced cognitive performance, and reduced cocaine craving. However, reduced levels of pregnenolone and androstanediol were associated with prolonged durations of cocaine use [59,60]. Pregnenolone supplementation significantly increases pregnenolone levels and effectively reduces stress and cocaine cue-induced craving and anxiety in individuals with CUD. Additionally, it demonstrates a notable reduction in stress-induced autonomic arousal [226].
Additionally, pregnenolone has emerged as a potent negative allosteric modulator of the CB1 receptor, effectively counteracting the effects of Δ9-tetrahydrocannabinol (THC), the primary active compound in Cannabis sativa (marijuana). This suggests a potential protective role against cannabis intoxication. Contrary to its conventional classification solely as a precursor to neurosteroids, evidence indicates that pregnenolone, rather than its downstream neurosteroids, mediates this inhibition of THC effects via CB1 receptors. Notably, THC administration significantly boosts pregnenolone synthesis in the brain through CB1 receptor activation, initiating a negative feedback loop where pregnenolone acts as a protective mechanism against CB1 receptor overactivation [202].
Importantly, AEF0117, also known as 3β-(4-methoxybenzyloxy)pregn-5-en-20-one, was engineered to be an unmetabolized derivative of pregnenolone, targeting selective inhibition of THC effects via the CB1 receptor. Preclinical studies in animals demonstrated reduced cannabinoid self-administration and THC-related impairment without significant adverse effects following AEF0117 treatment. Phase 1 trials in healthy volunteers confirmed the safety and tolerability of AEF0117, while phase 2a trials in individuals with cannabis use disorder showed significant reductions in cannabis subjective effects and self-administration without precipitating withdrawal. These findings suggest that AEF0117 could be a safe and effective treatment for cannabis use disorder [66].
Moreover, it is known that CB1 receptors can interact with TLR receptors, implying that inhibition of CB1 receptors by pregnenolone or its derivatives could also mitigate inflammatory TLR signaling [305,306].
Although the studies did not directly assess inflammation, the known anti-inflammatory properties of progesterone, allopregnanolone and pregnenolone suggest a potential area for future research in investigating their impact on inflammation in cocaine- and cannabis-dependent individuals. Moreover, further research is warranted to assess the effects of neurosteroid therapy on other substance use disorders where the field currently lacks sufficient information, such as nicotine and methamphetamine.
In summary, substance abuse, including alcohol and psychoactive drugs, can disrupt neuroimmune signaling, leading to neurodegeneration and behavioral issues in substance use disorders. Neuroactive steroid treatments, like allopregnanolone and pregnenolone, show promise in alleviating craving, anxiety, and stress-induced responses and inhibiting pro-inflammatory signaling while enhancing anti-inflammatory signaling. Future research should explore their potential anti-inflammatory effects and therapeutic applications across various substance use disorders.

3.3. Pain and Neurological Injuries

Neurological injuries, acute pain, chronic pain, migraines, neuropathic pain, and allodynia are associated with activation of both the adaptive and innate immune systems [182,184]. TLRs, particularly TLR4, regulate pain perception and prolongation through the expression of cytokines [396,397,398]. Sex-specific differences in pain perception have highlighted the necessity for tailored treatments [399,400]. Notably, sexual specificity is observed in pain related TLR signaling, where TLR4 inhibition directly modulates pain perception in males but not females [401,402].
Allodynia has been reversed in transgenic mice lacking TLR2, TLR3, TLR4, TLR5, or MyD88 genes, with MyD88-dependent pathway activation identified as the primary mediator of allodynia [401,403]. Although not specifically employing neuroactive steroids, the observed analgesic effect is attributed to the inhibition of the TLR–MyD88 pathways, like the mechanisms inhibited by allopregnanolone, pregnenolone, and progesterone [36,37,67,71].
Studies in rats have shown that progesterone treatment after spinal nerve injury led to a decrease in pain behavior and allodynia, along with reduced mRNA levels of IL-1β, IL-6, and TNF-α [404,405]. Allopregnanolone and progesterone have also demonstrated a decrease in acute NF-kB, IL-6, IL-1β, and TNF-α expression in TBI rat models [52,406,407,408]. Additionally, in ovariectomized female rats, estrogen and progesterone have been shown to reduce edema and cytokine expression observed in TBI [409,410].
Testosterone has been found to decrease pro-inflammatory cytokines and increase the anti-inflammatory cytokine IL-10 in males, providing protection against muscle pain in both females and males [411,412,413].
Emerging evidence from male and female Iraq/Afghanistan-era veterans suggests that decreased neurosteroid levels are associated with increased pain and TBI symptoms, indicating a potential role for neurosteroids as biomarkers [414,415,416].
Importantly, in the randomized, double-blind, placebo-controlled clinical trial involving male Iraq- and Afghanistan-era US military veterans with chronic low back pain, adjunctive treatment with pregnenolone showed significant promise. Participants who received pregnenolone reported a substantial reduction in pain intensity ratings after 4 weeks of treatment compared with those who received placebo. Additionally, pregnenolone treatment led to improvements in pain interference scores for work and activity. These findings suggest that pregnenolone may serve as a safe and effective adjunctive treatment for male veterans with chronic low back pain [417]. Further research and exploration into the long-term effects and optimal dosing of pregnenolone are warranted to fully elucidate its therapeutic potential in pain management.
In summary, pain and neurological injuries are closely tied to immune system activation, notably through TLR4. Sex-specific differences underscore the need for personalized, tailored treatments. Neuroactive steroids and hormones such as estrogen and testosterone offer promising avenues for pain management in neurological injuries.

3.4. Seizure Disorders

Seizures often coincide with several other disorders, including migraine with aura, alcohol dependence, pain, depression, and various neurological and psychological conditions [418,419,420,421]. Given the potentially life-threatening nature of seizures, much research has been directed towards managing seizure episodes rather than addressing the underlying disorders themselves. Consequently, numerous seizure models and treatments have been developed, primarily focusing on regulating neuronal signaling. GABAergic neuroactive steroids like allopregnanolone are proposed as anti-convulsants, while sulfite active steroids such as PS and DHEAS are known to have convulsant and epileptogenic properties [422,423].
The depletion and lower levels of neurosteroids have been implicated in seizures, as observed in conditions such as catamenial epilepsy, where seizures are more frequent during periods of low progesterone levels [424,425]. Treatments involving progesterone have shown promise in reducing seizure frequency in women with intractable catamenial epilepsy [426], with its anti-convulsant effects suggested to be mediated by metabolites such as 3α,5α-THDOC and primarily allopregnanolone [427,428,429,430].
These findings have led to clinical studies involving the exogenous β-methylated analog of allopregnanolone as an anti-convulsant. A recent meta-analysis by Meng et al. (2023) [431] reported the efficacy of ganaxolone in reducing seizure frequency by up to 50% for refractory seizures, leading to its FDA approval in 2022 for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDD) deficiency disorder [432]. In the open-label extension of the Marigold study (NCT03572933), ganaxolone showed sustained reductions in major motor seizure frequency over 2 years in patients with CDD. Most patients experienced significant improvements, with safety findings consistent with earlier phases, supporting ganaxolone’s efficacy and safety profile for CDD-associated seizures [433].
Interestingly, trilostane, a potent inhibitor of 3β-HSD, has recently been found to significantly increase levels of various neurosteroids, particularly allopregnanolone, both in the brain and peripherally. Notably, in the kainic acid model of temporal lobe epilepsy, trilostane treatment has demonstrated a remarkable ability to slow down epileptogenesis, resulting in a significant reduction in seizure occurrence compared with the control group receiving vehicle. These findings suggest that the trilostane-induced elevation of neurosteroids may possess a disease-modifying effect in epileptic brains [434,435].
While extensive research has explored the influence of neuroactive steroids on epileptogenesis, seizure frequency, and their modulation of neuronal currents via GABAergic signaling, emerging evidence indicates that the anti-inflammatory properties of neuroactive steroids could amplify their therapeutic potential for seizure management.
Mounting evidence underscores the pivotal role of immune and inflammatory processes in the onset and progression of seizures. Various triggers, including infection, febrile seizures, neurotrauma, and stroke, induce innate immune mechanisms and subsequent inflammatory responses in the brain, leading to acute symptomatic seizures and an increased risk of epilepsy [185,186,271,273,436]. Immune and glial cells, notably astrocytes and microglia, are central to these processes. During status epilepticus, activated astrocytes disrupt synaptic equilibrium, exacerbate excitotoxicity, and contribute to seizure occurrence [437,438]. Notably, stimulating the astrocytic inflammatory TLR4–MyD88–ERK pathway during early development induces excitatory synaptogenesis and increases susceptibility to seizures [439,440]. Microglia exhibit remarkable plasticity in transcription, morphology, and function, which dynamically evolve throughout the course of epilepsy [441]. Inhibiting the activation of astrocytic and microglial cells holds promise as a treatment strategy, necessitating the development of novel approaches with anti-inflammatory effects. These approaches aim to address the underlying inflammatory processes contributing to epilepsy [442,443].
Advancements in understanding the molecular intricacies of the innate immune system, particularly TLR signaling, have unveiled its significant contribution to seizure activity. Activation of TLR signaling results in increased production of various inflammatory modulators [187,271,272,444,445,446,447], along with rapid post-translational changes in ion channels that enhance excitability and transcriptional alterations in genes associated with neurotransmission and synaptic plasticity, ultimately reducing seizure thresholds chronically [186,448]. Experimental studies have demonstrated the critical role of TLR4 in seizure initiation and propagation, with its ligand HMGB1 emerging as a potential therapeutic target [440,449]. HMGB1, a member of the damage-associated molecular patterns family, is upregulated in experimental epilepsy models and interacts with TLR4 receptors, contributing to epilepsy pathophysiology [272]. Studies on TLR knockout mice and expression levels in epileptic patients further emphasize the involvement of TLR-dependent pathways in seizure development [274,450,451,452].
Recent studies have shown that allopregnanolone inhibits inflammatory MyD88-dependent TLR pathways, resulting in decreased production of MCP-1, TNF-α, IL-1β, IL-6, and HMGB1, and enhances the TRIF-dependent anti-inflammatory TLR4 pathway, resulting in increased production of IL-10 and BDNF in the brains of P rats. Allopregnanolone has been found to have similar effects in mouse and human macrophages [36,37,67,80]. This innovative finding highlights the potential of neurosteroids to influence the neuroimmune system through both MyD88-dependent and TRIF-dependent TLR pathways in epilepsy and a wide variety of conditions involving inflammation.

3.5. Neurodegenerative Diseases

Neuroinflammation is one of the hallmarks of the pathology of neurodegenerative disorders, and some evidence suggests a role of TLRs in mediating this inflammatory response. Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by the deterioration of dopaminergic neurons, leading to motor deficits such as tremors, bradykinesia, and rigidity [453]. Several studies have demonstrated TLR2 upregulation in both blood and brain postmortem tissue of PD patients, with enriched expression observed in neurons and microglia within the brain [454,455]. Other evidence reports increased proinflammatory cytokines, including TNF-α, IL-1β, IL-2, IL-4, and IL-6, in blood, brain, and CSF of PD patients [455,456]. Furthermore, as the prevalence of PD is nearly two times higher in men than in women [457,458,459], it has led to the hypothesis that female sex hormones might play a protective role against the factors contributing to PD pathology [460,461]. In line with this, several neurosteroids have been implicated as potentially beneficial therapeutics for the treatment of PD.
First, allopregnanolone and 5α-dihydroprogesterone, but not progesterone, levels in plasma and CSF are downregulated in PD patients relative to healthy individuals [462]. Allopregnanolone also restored degraded TH-immunoreactive neurons in the nigrostriatal tract and improved balance and motor coordination in a PD model mouse (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesion) [463]. As a further example, allopregnanolone improved motor impairments and reduced COX-2 levels in a 6-hydroxydopamine (6-OHDA) model rat [464]. Progesterone, a precursor to allopregnanolone, was shown to be neuroprotective against 6-OHDA and 1-methyl-4-phenylpyridinium-induced cell death in an SH-SY5Y neuronal cell line [465]. Furthermore, progesterone reversed the loss of striatal dopamine, dopamine and vesicular monoamine transporters and prevented the loss of BDNF and the increase of GFAP [466]. As for androstane steroids, DHEA treatment rescued depleted TH-positive neurons and recovered ERK phosphorylation [467]. ADIOL ameliorated rotenone-induced elevation of NF-κB and expression of iNOS and IL-6 [311]. Taken together, these studies suggest a potential protective role of pregnane and androstane steroids in PD pathology, in part, through neuroimmune regulation.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deterioration of cognition and memory and associated with the accumulation of amyloid-beta and tau proteins [468]. It is well-known that neuroinflammation contributes to the pathogenesis of AD. Specifically, microglial activation is induced by the presence of amyloid-beta plaques as an attempt to phagocytose and clear these plaques [469,470]. Proinflammatory signaling molecules, such as TNF-α, IL-1β, and IL-6, play central roles in AD pathology [471,472]. TNF-α and IL-1β levels have been reported to be enriched in the brains and blood of AD patients [473,474,475]. The release of these cytokines by activated microglia contributes to the amplification of neuroinflammation and exacerbates synaptic dysfunction [476]. Moreover, the presence of inflammatory signaling molecules is identified as a risk factor for the development of AD [477,478]. As neurosteroids have been shown to confer therapeutic benefit in the context of neuroinflammatory mediation, there is evidence to suggest they may be a treatment option for AD.
In fact, in preclinical rodent studies, allopregnanolone reduced amyloid-beta accumulation, increased the survival of neural progenitors, restored memory and learning performance, and decreased microglial activation in an AD-model mouse [479,480,481]. In clinical studies, allopregnanolone is currently being investigated in a phase II trial as a potential regenerative therapy in AD patients, with a particular focus on assessing hippocampal volume and cognition (NCT04838301) [81]. Preliminary results from a phase I trial suggest that allopregnanolone is well tolerated and safe in patients with AD [482]. As the reduction in estrogen in postmenopausal women is a risk factor for the development of AD, it raises the question of whether female sex hormones may be protective against AD pathogenesis [483,484]. Indeed, AD depletion of estrogen and progesterone via ovariectomy in rodents results in worsening of AD-like pathology, but estrogen treatment prevents this worsening. However, progesterone treatment has contrasting effects as it does not ameliorate amyloid-beta accumulation but does reduce tau phosphorylation [485]. The protective role of female sex hormones is well-documented, and their potential therapeutic benefit in AD remains to be further clarified. Other neurosteroids have been implicated in AD, as DHEAS concentrations are found to be lower in AD patients relative to control, whereas DHEA levels are not different [486,487]. In fact, DHEA treatment did not improve cognitive performance in a clinical study with patients with AD [488]. Interestingly, it was found that high DHEAS levels were associated with faster cognitive decline, and the ratio of cortisol/DHEAS is positively correlated with tau accumulation [489]. This apparent contradiction reflects the complex relationship between different neurosteroids with distinct actions and AD pathology. Finally, investigations into the therapeutic potential of 3α,5α-THDOC for AD have found that 3α,5α-THDOC reduces amyloid-plaque accumulation and size in an AD model rat [490]. Taken together, these studies highlight the potential for some neurosteroids to regulate neuroimmune and inflammatory processes, holding promise for their broader application in the treatment of neurodegenerative disorders.

3.6. Neurodevelopmental Disorders and Autism Spectrum Disorder (ASD)

Neurodevelopmental disorders, including autism spectrum disorder (ASD), result from a complex interplay of genetic, mental, and environmental factors [491]. Prenatal exposures such as stress, drugs, and viruses, along with preterm birth and childhood experiences, can significantly impact the immune system. Notably, during pregnancy, elevated levels of estrogen and progesterone stimulate the expression of anti-inflammatory cytokines such as transforming growth factor (TGF)-β, IL-4, and IL-10 [492]. Research in rats indicates that the fetal immune state closely resembles that of the mother [493], and neuroactive steroids are transferred from the mother’s placenta to the fetus and also synthesized within the fetal organism [494]. This phenomenon explains the increased concentrations of progesterone and allopregnanolone following birth compared with the fetal phase [495]. Elevated levels of allopregnanolone, progesterone, IL-6, and IL-10 at birth have been associated with issues such as poor myelination, low birth weight, increased mortality, and encephalopathy among preterm newborns [495,496]. Subcutaneous administration of ganaxolone, a β-methylated analog of allopregnanolone, in preterm guinea pigs provided protection against the loss of myelination, hyperactive behavior, and premature mortality observed in untreated preterm control animals [497], highlighting the neuroprotective potential of allopregnanolone in mitigating neurodevelopmental disorders associated with preterm births.
ASD is a multifaceted neurodevelopmental condition influenced by genetic, environmental, and immune factors. Recent research suggests immune dysregulation may contribute significantly to its etiology. Elevated cytokine levels have been observed in both the peripheral and nervous systems of individuals with ASD [498], indicating potential immune involvement. Furthermore, studies have found heightened cytokine levels in brain tissue and spinal fluid of ASD patients [499,500]. Chew and Peers (2021) [501] proposed that disrupted neurosteroid production, particularly low levels of allopregnanolone, could contribute to immune and neurodevelopmental dysfunction in ASD. Clinical trials have shown that the neurosteroid pregnenolone can improve irritability, stereotypy, and hyperactivity in adolescents with ASD [502]. However, the impact of these steroids on the immune system remains understudied. Given the promising outcomes of neuroactive steroid treatments in mitigating ASD symptoms associated with impaired immune activation, further investigation into their regulatory role in the immune system is warranted.

4. Limitations and Challenges

4.1. Constraints and Potential Side Effects of Neurosteroid Therapy

The therapeutic use of neuroactive steroids has emerged as a promising avenue for the modulation of neuroimmune responses, offering a novel approach to address various neurological and psychiatric disorders. However, like any therapeutic intervention, the use of neurosteroids is not without its constraints and potential side effects. Understanding these limitations is crucial for the development and optimization of neurosteroid-based treatments.
For many years, therapy with allopregnanolone and other neuroactive steroids has raised greater caution by the scientific community given their positive modulation of GABAA receptors. First, neurosteroid therapy increases endogenous neuroactive steroid levels, by increasing the substrates for steroidogenesis. This could lead to the production of other neurosteroids, with the same positive action on the GABAergic system or the opposite effects. For example, it has been demonstrated that administration of pregnenolone in rats induces the production of the GABAergic positive modulator, pregnanolone (3α,5β-3-hydroxypregnan-20-one), normally undetectable in rodents [503].
Second, it is well known that social drugs such as alcohol and nicotine can increase the levels of GABAergic neurosteroids [504,505,506]. The increase in these neurosteroids may interact with alcohol and nicotine, leading to deleterious effects that can affect important abilities such as driving or operating machinery. Moreover, several studies have shown that neuroactive steroids may increase alcohol reinforcement, consumption, and reinstatement of drinking in animal models of alcohol addiction, depending on the dose [48,507,508,509,510]. A recent study also unveiled a possible deleterious interaction between allopregnanolone administration and opioid system activation during forced swim stress in rats [511]. This result suggests the need for further studies to address potential limitations of allopregnanolone for psychiatric disorders involving HPA axis activation.
Moreover, allopregnanolone has been shown to promote cell proliferation in a human glioblastoma (GB) U87 multiforme cell line and the expression of genes associated with tumor progression, including TGF-β1, epidermal growth factor receptor, vascular endothelial growth factor, and cylin-D1 [512]. Additionally, allopregnanolone was shown to increase the migration and invasion of GB cells, potentially through the activation of the cellular proto-oncogene tyrosine-protein kinase Src pathway [513]. These results are further supported by the fact that sex steroid hormones, including estrogens and progestins, can induce the progression of GBs [514,515]. In the IGROV-1 ovarian cancer cell line, allopregnanolone increased cell proliferation, Ki67 expression, and cell migration [516]. Importantly, the primary literature surrounding the relationship between neurosteroids and cancer is very mixed, as allopregnanolone activation of membrane progesterone receptors (mPRs) decreased starvation-induced cell death and apoptosis in mPRδ-transfected cells and neuronal cells, suggesting a possible protective role [517]. These findings raise concerns about the potential role of allopregnanolone in promoting tumor progression; however, further research is needed to fully understand these implications and determine whether allopregnanolone may contribute to cancer development or progression in vivo. Additionally, it should be noted that the role of neurosteroids in cancer is likely dependent on various factors such as the type of cancer and the specific cellular context.
Another concern is that therapy with allopregnanolone and other neuroactive steroids may lead to untoward effects, such as dependence and/or addiction, especially in patients with deficient GABAergic transmission, as seen in individuals with AUDs. Considering that therapy with neuroactive steroids may be a lifelong treatment for some patients, this possibility needs to be considered, and more studies need to be conducted to evaluate the long-term effects of neurosteroid therapy. In fact, it is well known that progesterone withdrawal can lead to anxiety and GABAA receptor dysregulation in animals [518,519,520,521], suggesting that rapid allopregnanolone withdrawal may occur as well in human subjects. Potential side effects, tolerance development, and abuse potential of some neurosteroids are crucial aspects that remain to be fully clarified, and ongoing research is actively contributing to our evolving understanding of these factors.
As some neurosteroids are modulators of GABAA receptors, a common side effect of neurosteroid treatment is sedation. In fact, patients receiving brexanolone therapy have reported fatigue, dizziness, sleepiness, dry mouth, flushes, and loss of consciousness [522]. Tolerance is known to develop after long-term exposure to GABAA receptor agonists [523,524]. Indeed, allopregnanolone has been shown to induce both acute and chronic tolerance by decreasing the expression of GABAA receptor subunits [525,526,527]. This underscores the potential for neurosteroids to change GABAA receptor sensitivity, necessitating careful management to mitigate potential tolerance and maintain treatment efficacy.
At present, neurosteroids hold FDA approval solely for acute therapeutic interventions, mitigating concerns regarding tolerance and dependence. Brexanolone, for instance, is approved for a 60 h infusion [528], and zuranolone is approved as a 14-day oral medication [529]. However, in instances where chronic administration of neurosteroids might be necessary, close monitoring may be warranted regarding the potential development of tolerance and/or dependence.
In summary, short-term neurosteroid therapy shows promise in modulating neuroimmune responses for neurological and psychiatric disorders, yet its chronic use likely entails constraints and potential side effects. Increased neurosteroid levels might lead to unpredictable effects, including interactions with social drugs like alcohol or nicotine. Additionally, concerns arise regarding the long-term effects and tolerance development associated with neurosteroid treatment. Ongoing research is essential to address these concerns and optimize the safety and efficacy of neurosteroid-based therapies.

4.2. Ethical and Regulatory Considerations for Neuropsychiatric Treatment

An estimated 22.8% of adults in the United States present with a mental, behavioral, or emotional disorder. While current treatment options exist, they are often ineffective in addressing the complex and heterogeneous nature of these disorders. As an example, for patients with MDD, only a third of patients experience significant symptom improvement with conventional therapies [530,531]. Thus, there is an ever-growing interest in novel therapeutics and emerging therapies for the treatment of psychiatric disorders. This includes the investigation of neurosteroids, which show immense promise for neuropsychiatric treatment.
Drug development is a high-cost, high-risk, and long process that has a staggering failure rate of 90% [532,533]. The estimated average cost of drug development ranges from USD 1.349 billion to USD 1.706 billion [534] and takes, on average, 10–15 years until approval [532]. Notably, neurological and psychiatric drugs face particularly daunting odds in gaining approval, with phase I clinical trials showing approval rates of 8.4% and 6.2%, respectively [535]. However, the challenges peak in phase II, where most clinical trials fail with an approximate 70% failure rate attributed to drug efficacy issues or significant off-target effects in patients [536,537,538]. Given these regulatory barriers, it is unsurprising that the number of drugs on the market and in phase III for psychiatric indications is low, and there exists a critical need for neuropsychiatric therapeutics. For psychiatric disorders in particular, the high failure rate is due, in part, to poor understanding and complexity of the pathophysiology of these disorders. Animal models, while invaluable, can have poor translational value for drug discovery research due to neuroanatomical differences and the limitations of behavioral assays [539]. Off-target effects and individual differences may also contribute to the challenges of predicting drug responses in clinical populations. The heterogeneity in presentation of psychiatric conditions and patient response to treatments can contribute to the apparent failures to meet specific endpoints in clinical trials [540]. Metrics for assessing symptom improvement in patients are often not sensitive enough to parse out specific benefits and can obscure the nuanced impact of treatments on various facets of psychiatric health.
Even after FDA approval of a drug, barriers to patient access to treatment arise as the financial cost of novel therapeutics is often significantly higher than that of traditional therapies, raising ethical concerns. For example, the introduction of novel neuropsychiatric treatments, such as brexanolone (a formulation of the neurosteroid allopregnanolone) for PPD, comes with a substantial cost of approximately USD 34,000 [541]. This financial burden is further compounded by the additional cost of hospitalization during the required 60 h infusion period [522]. However, brexanolone has demonstrated remarkable efficacy in alleviating PPD symptoms, outperforming a placebo group based on HAM-D scores [62,358]. The accessibility of brexanolone treatment is further hindered by logistical challenges. Prolonged hospitalization during infusion can pose challenges for individuals who may face difficulties in managing the associated disruptions to life, work commitments, and childcare responsibilities. To address this challenge, there is a new oral formulation of brexanolone, zuranolone, introduced as an alternative. However, the financial strain remains substantial even with this option as it is priced at USD 15,900 without insurance [542]. Given the high efficacy of these treatments, one might suggest that the economic and personal burden incurred by postpartum depression through inability to work, etc., might be higher than treatment with brexanolone. Patients and physicians must choose between the acute, high cost associated with potentially efficacious and rapid symptom alleviation or opt for the comparatively lower cost of traditional treatments that may be less efficacious and administered long-term. As low socioeconomic status is a risk factor for PPD [543], it is important to recognize that these high treatment costs can perpetuate health disparities. This situation underscores a pressing ethical concern regarding equitable access to healthcare.

5. Future Directions in Neurosteroid Research

The complexities of both systemic and neuroimmune signaling in neuropsychiatric diseases have brought attention to the emerging field of neurosteroid treatment research. The pharmacological properties of neuroactive steroids show promising applications due to their modulatory effects on a wide array of mechanisms. Within this review, we have examined previous findings and discussed the implications of neuroimmune modulation orchestrated by endogenous neurosteroids. However, many new avenues are yet to be explored, offering opportunities for innovation and discovery in the neurosteroid field.
Using traditional techniques such as co-immunoprecipitation, western blotting, and ELISAs, significant progress has been achieved in understanding the impact of neurosteroids on inflammatory TLR signaling pathways. For example, pregnane neurosteroids such as allopregnanolone and pregnenolone have demonstrated inhibitory effects on the binding of TLR2, TLR4, and TLR7 with MyD88. Additionally, they inhibit the binding of TLR4 with MD2 or the α2 subunit of GABAA receptors. This understanding has provided valuable insights into the downstream effects on inflammatory-driven proteins, leading to the reduction of inflammatory chemokines and cytokines [36,37,67]. As previously noted, brexanolone, an intravenous formulation of allopregnanolone, has shown effectiveness in inhibiting the production of TNF-α, IL-1β, and IL-6 induced by the TLR4 agonist LPS and the TLR7 agonist imiquimod. This inhibition serves as an indicator of TLR4 and TLR7 signaling pathway suppression [64].
However, the exact molecular mechanisms and binding modalities behind these events have not yet been fully determined. Integrating complementary approaches such as computational modeling and molecular docking [544,545], surface plasmon resonance [546,547], cryo-electron microscopy [548,549], along with site-directed mutagenesis of target proteins [550], can provide a comprehensive understanding of these mechanisms. This integration paves the way for the development of novel therapeutic strategies targeting inflammatory signaling pathways.
MyD88 serves not only as a signaling protein in TLR pathways but also plays a crucial role in IL-1 receptor (IL-1R) signaling, which constitutes another significant neuroimmune signaling cascade. Presently, there are ongoing drug discovery endeavors concentrating on IL-1R pathways and related proteins like MyD88. This provides a solid foundation for advancing neurosteroid research within neuroimmune signaling [551,552,553]. Once these pathways are thoroughly understood, it opens the door to innovative avenues such as repurposing neurosteroids, exploring new synthetic analogs, and conducting ligand- or structure-based virtual screenings of neurosteroid-protein binding sites. Such initiatives hold the potential to uncover more effective and beneficial compounds for therapeutic use.
Despite their advantageous properties in alleviating neuroimmune signaling and GABAergic and other neurotransmission system modulation, the pharmacological and physicochemical properties of neurosteroids contain room for improvement for treatment purposes. The structural requirements for the anti-inflammatory properties of the pregnane neurosteroids have not been fully delineated but appear to involve the integrity of the D ring structure of pregnenolone, progesterone and allopregnanolone. Modifications of the D ring at C21 appear to reduce TLR inhibition in mouse and human macrophages as well as rat brain [36,37,67], but this modification does not impair increases in the anti-inflammatory modulators IL-10 and fractalkine observed in P rat brains [80,302]. The structural prerequisites for neurosteroid modulation of GABAA receptors involve a hydrogen bond-donating 3α-hydroxy group on the steroid A-ring and a hydrogen bond-accepting group on the D ring, either at C20 of the pregnane steroid side chain or at C17 of the androstane ring [9,25,215]. Additionally, the orientation of the C5 hydrogen group is crucial for increased potency, though less so for activity [9,215]. Although advantageous, endogenous neurosteroids have been shown to have poor aqueous solubility, low bioavailability, quick metabolic turnover, and a rather short half-life [51,554].
To overcome these challenges, research teams have devised methods to develop neurosteroid analogs possessing more advantageous physicochemical properties, thus broadening the scope through structure–activity relationship investigations. Such efforts have culminated in the synthesis of more favorable allopregnanolone analogs, including the FDA-approved zuranolone and ganaxolone, for the treatment of postpartum depression and seizures, respectively. Zuranolone was identified through C-21 modifications of 5β-nor-19-pregnan-20-one, while ganaxolone was derived from the addition of a methyl substitution in the β-orientation, aimed at mitigating the rapid oxidation of the 3α-hydroxy group of allopregnanolone [555,556,557].
A library of pregnenolone derivatives was synthesized and evaluated in cell cultures to identify compounds that resisted metabolism into other steroids by endogenous enzymes. AEF0117 [3β-(4-methoxybenzyloxy)pregn-5-en-20-one] stood out among these derivatives and displayed optimal pharmacokinetic characteristics, brain penetrance, selectivity, and safety profile, positioning it as a promising candidate for therapeutic intervention targeting the endocannabinoid system [66].
With these three exemplary instances leading the charge in synthetic pregnane class neurosteroid-based therapies, the realm of potential future discoveries remains promising.
Integrating chemical biology for clickable and photoactivatable neurosteroid probe synthesis, along with chemoproteomics to map neurosteroid-protein interactions in live cells, is crucial for advancing targeted therapies. By employing clickable and photoactivatable probes, researchers can selectively label neurosteroid-binding proteins within live cells, allowing for precise mapping of these interactions. Furthermore, by integrating chemoproteomics, researchers can comprehensively profile neurosteroid-protein interactions across different cell types, providing a deeper understanding of the cellular response to neurosteroids [303,304]. However, there is a limitation to using such modified neurosteroids with linkers, as they may reduce neurosteroid potency. Endogenous neuroactive steroid 3α,5α-THDOC and synthetic neuroactive steroid SGE-516 (Sage Therapeutics, Inc., Cambridge, MA, USA) [558] exhibited lower effectiveness in inhibiting TLR4 and TLR7 pathway activation in macrophages from female donors compared to allopregnanolone. This discrepancy in effectiveness is influenced by structural variances, particularly in the C-21 position with hydroxyl or triazole groups [37].
The sex-specific effects of pregnane neurosteroids, particularly in modulating TLR pathway signaling, are of significant interest due to their dual roles in inhibiting inflammatory responses and enhancing anti-inflammatory responses. Understanding the structural requirements for these effects is crucial for developing targeted therapies. 3α,5α-THDOC and SGE-516 inhibits TLR4 and TLR7 pathway activation in macrophages from female donors but not from male donors [37]. Additionally, allopregnanolone has been found to enhance anti-inflammatory TLR4 signaling and increase IL-10 levels in male P rat brains but not female P rat brains [80]. These findings highlight the need for further research to identify other natural and synthetic compounds that mimic the anti-inflammatory activities of endogenous pregnane neurosteroids. Developing compounds with similar properties could lead to targeted therapies for inflammatory conditions, considering sex-specific responses and structural requirements for optimal efficacy.
In summary, the field of neurosteroid treatment research presents a promising avenue for addressing the intricate mechanisms involved in neuropsychiatric diseases. By combining traditional techniques with advanced methodologies such as chemical biology and chemoproteomics, researchers can gain valuable insights into neurosteroid–protein interactions within live cells. Furthermore, the sex-specific effects of pregnane neurosteroids on inflammatory pathways highlight the importance of considering biological variability in therapeutic development. Despite these challenges, continued exploration of neurosteroids holds great promise for advancing our understanding of neuropsychiatric disorders and developing effective treatment strategies tailored to individual patient needs.

6. Conclusions

Neurosteroid therapy shows promise in modulating neuroimmune and immune responses in neurological and psychiatric disorders. Notably, pregnane neuroactive steroids like allopregnanolone and pregnenolone exhibit potent anti-inflammatory effects by influencing TLR activation and its associated signaling pathways. These steroids effectively suppress pro-inflammatory MyD88-dependent TLR signal activation through specific mechanisms, disrupting essential protein–protein interactions necessary for TLR activation and decreasing the production of pro-inflammatory factors. Specifically, they block the binding of TLR2, TLR4, and TLR7 with MyD88, as well as the binding of TLR4 with MD2 and the α2 subunit of GABAA receptors. This inhibition prevents the initiation of inflammatory TLR pathways, resulting in reduced levels of TRAF6 and diminished activation of TAK1, NF-κB, and MAPK/ERK1/2. Consequently, this inhibits the activation of various transcription factors, including CREB, STAT1, ATF2, and IRF7, leading to a decrease in inflammatory mediators such as MCP-1, TNF-α, IL-6, IL-1β, and HMGB1. Moreover, pregnane neuroactive steroids may attenuate inflammatory TLR signaling by promoting the ubiquitination and degradation of TLRs and TLR adapter proteins like TIRAP, as well as by modulating CB1 receptors that potentially interact with TLRs.
Additionally, progesterone suppresses pro-inflammatory TLR activation by increasing IκBα expression, thereby reducing NF-κB phosphorylation and nuclear translocation. It also diminishes the expression of TLRs, MyD88, and CD14, resulting in decreased production of inflammatory cytokines. Direct effects of progesterone on TLR activation have not yet been studied, but it is highly likely that inhibition could be observed, based on the structural similarities to pregnenolone and allopregnanolone at the C and D rings. Further studies are warranted to address this possibility.
Conversely, allopregnanolone enhances anti-inflammatory TRIF-dependent TLR4 signaling in a sex-specific manner, resulting in increased production of anti-inflammatory cytokines and neurotrophic factors such as IL-10 and BDNF. This intricate process involves several steps: allopregnanolone triggers the translocation of TLR4 from the plasma membrane to endosomes by upregulating the p110δ isoform of PI3K and degrading TIRAP. Consequently, there is an accumulation of TLR4 and TRIF, forming a complex within endosomes, thereby activating the anti-inflammatory signaling cascade. Furthermore, allopregnanolone enhances this pathway by increasing activated TRAM levels, leading to upregulation of the transcription factor SP1 and subsequent IL-10 production. Additionally, allopregnanolone elevates BDNF levels, potentially amplifying IL-10 production and release. Moreover, allopregnanolone stimulates the accumulation of endosomal Ras-related protein Rab7, suggesting a role in influencing the equilibrium between pro-inflammatory and anti-inflammatory TLR4 signaling pathways.
The inhibition of inflammatory TLR pathways and enhancement of anti-inflammatory TLR pathways by allopregnanolone have been observed in the brains of alcohol-preferring rats with innately activated TLR pathways, as well as in mouse and human macrophages and mouse microglial cells activated by TLR ligands.
Of significance is the demonstrated inhibition of inflammatory TLR4 and TLR7 pathways by allopregnanolone (brexanolone) in whole blood cells obtained from individuals with PPD. These were accompanied by symptom improvements. Specifically, brexanolone infusion reduced whole blood cell TNF-α and IL-6, and these effects were correlated with HAM-D score improvement. Furthermore, brexanolone infusion prevented LPS- and imiquimod-induced elevation of TNF-α, IL-1β, and IL-6 in vitro in PPD whole blood cells, indicating inhibition of TLR4 and TLR7 responses. Finally, inhibition of TNF-α, IL-1β, and IL-6 responses to both LPS and imiquimod were correlated with HAM-D score improvements (see Table 1).
Androstane neuroactive steroids, including estrogens, androgens, DHEA, and ADIOL, exert diverse effects on TLR expression and activation, contingent upon the context and specific diseases. ADIOL shows promise as a potent anti-inflammatory agent, while estrogens and androgens exhibit both anti-inflammatory and pro-inflammatory effects on TLRs. DHEA modulates immune responses via TLR activation, although its effectiveness in certain models remains limited and its impact on TLR expression yields complex outcomes.
Under various neuropsychiatric conditions, neuroimmune signaling, involving intricate communication between neuronal and glial cells, becomes disrupted to varying extents, depending on the severity of the disease. This disruption often results in the upregulation of inflammatory TLR ligands and the overactivation of inflammatory TLR signaling pathways, leading to an imbalance in pro-inflammatory and anti-inflammatory factors, favoring the former. Neuroactive steroids like allopregnanolone possess the ability to inhibit inflammatory TLR pathways and promote anti-inflammatory ones. This capability may help maintain homeostatic balance between inflammatory and anti-inflammatory factors in both the brain and periphery.
In numerous neuropsychiatric disorders, there’s an observed overactivation of inflammatory TLR pathways alongside reduced levels of endogenous neurosteroids. While direct studies demonstrating neurosteroid modulation of TLR pathways are primarily seen in conditions like PPD, it is reasonable to hypothesize that administering neurosteroids could, to some extent, improve neuropsychiatric outcomes by modulating TLR activity across various neuropsychiatric disorders (see Table 1). Further research in this direction is imperative for a comprehensive understanding and the development of potential therapeutic strategies.

7. Patents

ALM and IB hold a provisional patent on the anti-inflammatory effects of pregnane neurosteroids.

Author Contributions

Conceptualization: I.B.; Literature Review: I.B., G.B., S.L.C., M.H.M. and A.G.L.; Drafted manuscript: I.B., G.B., S.L.C., M.H.M., A.G.L. and A.L.M.; All authors edited and approved the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This review was partially funded by the NIH grant P60-AA011605 and the Bowles Center for Alcohol Studies at the UNC School of Medicine.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

5α-DHDOC/5β-DHDOC: 5α- or 5β-dihydrodeoxycorticosterone; 5α-DHP/5β-DHP: 5α- or 5β-dihydroprogesterone; 3α,5α-THDOC: 3α,5α-tetrahydrodeoxycorticosterone or [3α,5α]-3,21-dihydroxypregnan-20-one; 3α,5α-THP: (3α,5α)3-hydroxypregnan-20-one or 3α,5α-tetrahydroprogesterone or allopregnanolone; 3α,5β-THP: (3α,5β)3-hydroxypregnan-20-one or 3α,5β-tetrahydroprogesterone or pregnanolone; 3α-HSD/3β-HSD: 3α- or 3β-hydroxysteroid dehydrogenase; 3α-diol: androstanediol; 3α,5β-PC: 3α,5β-20-oxo-pregnane-3-carboxylic acid; 3β,5β-THP: Epiallopregnanolone; 17β-HSD: 17β-hydroxysteroid dehydrogenases; 6-OHDA: 6-hydroxydopamine; AD: Alzheimer’s disease; ADIOL: androstenediol or 5-androstenediol or 5α-androstane-3β,17β-diol; AEF0117: 3β-(4-methoxybenzyloxy)pregn-5-en-20-one; Akt: protein kinase B; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AR: Androgen receptors; ASD: Autism spectrum disorder; ATF2: Activating transcription factor 2; AUD: Alcohol use disorder; BDNF: Brain-derived neurotrophic factor; BPD: Bipolar disorder; CB1: cannabinoid receptor type 1; CD14: Cluster of differentiation 14 protein; CDD: cyclin-dependent kinase-like 5; CNS: Central nervous system; COX-2: Cyclooxygenase-2; CREB: Cyclic adenosine monophosphate response element-binding protein; CRF: Corticotropin-releasing factor; CSF: Cerebrospinal fluid; CYP11A1: Cytochrome P450scc or cholesterol side-chain cleavage enzyme; CYP21A2: Cytochrome P450 21A2 or 21-hydroxylase; CUD: Cocaine use disorder; CX3CL1: C-X3-C motif chemokine ligand 1 (Fractalkine); DHEA: Dehydroepiandrosterone; DHEAS: Dehydroepiandrosterone sulfate; DHT: Dihydrotestosterone; DOC: Deoxycorticosterone; EPS: exopolysaccharide; ER: Estrogen receptor; ERK: Extracellular signal-regulated kinase; FDA: Food and Drug Administration; GABAA receptor: Gamma-aminobutyric acid receptor type A; GB: Glioblastoma; GFAP: Glial fibrillary acidic protein; HAM-D: Hamilton Rating Scale for Depression; HMGB1: High mobility group box 1; HPA: Hypothalamic-pituitary-adrenal; IFN: interferon; IκB: Inhibitor of kappa-B; IKK: IκB kinase; IL: Interleukin; IL-1R: Interleukin-1 receptor; iNOS: inducible nitric oxide synthase; IRAK: Interleukin-1 receptor-associated kinase; IRF: IFN regulatory factor; JNK: c-Jun N-terminal kinase; LPS: Lipopolysaccharide; MAP2: Microtubule-associated protein 2; MAPKs: Mitogen-activated protein kinases; MCP-1: Monocyte chemotactic protein-1; MD2: Myeloid differentiation protein 2; MDD: Major depressive disorder; mPRs: Membrane progesterone receptors; MS: Multiple Sclerosis; MyD88: Myeloid differentiation primary response 88; NF-κB: Nuclear factor kappa-B; NMDA: N-methyl-D-aspartate; NO: Nitric oxide; p: phosphorylated; P: alcohol-preferring; PBMC: Peripheral blood mononuclear cells; PD: Parkinson’s disease; PI3K: Phosphoinositide 3-kinase; PPD: Postpartum depression; PS: Pregnenolone sulfate; PtdIns(4,5)P2: Phosphatidylinositol-(4,5)-bisphosphate; PTSD: Post-traumatic stress disorder; Rab7: Ras-related protein Rab7; S100β: S100 calcium-binding protein B; SOCS: Suppressor of cytokine signaling; SP1: Specificity protein 1; STAT1: Signal transducer and activator of transcription 1; TAK1: Transforming growth factor beta-activated kinase 1; TBI: Traumatic brain injury; TGF: Transforming growth factor; TH: Tyrosine hydroxylase; THC: Δ9-tetrahydrocannabinol; THDOC: Tetrahydrodeoxycorticosterone ([3α,5α]-3,21-dihydroxypregnan-20-one 3α,5α-THDOC); TIRAP: Toll/interleukin-1 receptor domain-containing adapter protein; TLR: Toll-like receptor; TNF: Tumor necrosis factor; TRAF: TNF receptor-associated factor; TRAM: TRIF-related adapter molecule; TRIF: IFN-β toll/interleukin-1 receptor domain-containing adapter-inducing.

References

  1. Lurie, D.I. An Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain. J. Exp. Neurosci. 2018, 12, 1179069518793639. [Google Scholar] [CrossRef] [PubMed]
  2. Dunn, G.A.; Loftis, J.M.; Sullivan, E.L. Neuroinflammation in psychiatric disorders: An introductory primer. Pharmacol. Biochem. Behav. 2020, 196, 172981. [Google Scholar] [CrossRef] [PubMed]
  3. Sun, Y.; Koyama, Y.; Shimada, S. Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation? Front. Aging Neurosci. 2022, 14, 903455. [Google Scholar] [CrossRef]
  4. Millett, C.E.; Burdick, K.E.; Kubicki, M.R. The Effects of Peripheral Inflammation on the Brain—A Neuroimaging Perspective. Harv. Rev. Psychiatry 2022, 30, 54–58. [Google Scholar] [CrossRef] [PubMed]
  5. Najjar, S.; Pearlman, D.M.; Alper, K.; Najjar, A.; Devinsky, O. Neuroinflammation and psychiatric illness. J. Neuroinflamm. 2013, 10, 816. [Google Scholar] [CrossRef] [PubMed]
  6. Cervellati, C.; Trentini, A.; Pecorelli, A.; Valacchi, G. Inflammation in Neurological Disorders: The Thin Boundary between Brain and Periphery. Antioxid. Redox Signal. 2020, 33, 191–210. [Google Scholar] [CrossRef]
  7. Paul, S.M.; Purdy, R.H. Neuroactive steroids. FASEB J. 1992, 6, 2311–2322. [Google Scholar] [CrossRef]
  8. Purdy, R.H.; Moore, P.H.; Morrow, A.L.; Paul, S.M. Neurosteroids and GABAA receptor function. In GABAergic Synatic Transmission; Biggio, G., Concas, A., Costa, E., Eds.; Raven Press: New York, NY, USA, 1992; pp. 87–92. [Google Scholar]
  9. Purdy, R.H.; Morrow, A.L.; Blinn, J.R.; Paul, S.M. Synthesis, metabolism, and pharmacological activity of 3 alpha-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes. J. Med. Chem. 1990, 33, 1572–1581. [Google Scholar] [CrossRef]
  10. Baulieu, E.E.; Robel, P.; Vatier, O.; Haug, A.; Le Goascogne, C.; Bourreau, E. Neurosteroids: Pregnenolone and Dehydroepiandrosterone in the rat brain. In Receptor-Receptor Interactions: A New Intramembrane Integrative Mechanism; Macmillan: London, UK, 1987; pp. 89–104. [Google Scholar]
  11. Boero, G.; Porcu, P.; Morrow, A.L. Pleiotropic actions of allopregnanolone underlie therapeutic benefits in stress-related disease. Neurobiol. Stress 2020, 12, 100203. [Google Scholar] [CrossRef]
  12. Morrow, A.L.; Boero, G.; Porcu, P. A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies. Alcohol. Clin. Exp. Res. 2020, 44, 320–339. [Google Scholar] [CrossRef]
  13. Morrow, A.L.; Balan, I.; Boero, G. Mechanisms Underlying Recovery From Postpartum Depression Following Brexanolone Therapy. Biol. Psychiatry 2022, 91, 252–253. [Google Scholar] [CrossRef] [PubMed]
  14. Tsutsui, K.; Ukena, K.; Takase, M.; Kohchi, C.; Lea, R.W. Neurosteroid biosynthesis in vertebrate brains. Comp. Biochem. Physiol.—Part C Toxicol. 1999, 124, 121–129. [Google Scholar] [CrossRef]
  15. Tsutsui, K. Neurosteroids in the Purkinje cell: Biosynthesis, mode of action and functional significance. Mol. Neurobiol. 2008, 37, 116–125. [Google Scholar] [CrossRef] [PubMed]
  16. Baulieu, E.E.; Robel, P.; Schumacher, M. Neurosteroids: Beginning of the story. Int. Rev. Neurobiol. 2001, 46, 1–32. [Google Scholar] [CrossRef]
  17. Agis-Balboa, R.; Pinna, G.; Zhubi, A.; Veldic, M.; Costa, E.; Guidotti, A. Location and expression of brain enzymes catalyzing neurosteroid biosynthesis. Proc. Natl. Acad. Sci. USA 2006, 103, 14602–14607. [Google Scholar] [CrossRef] [PubMed]
  18. Agis-Balboa, R.C.; Guidotti, A.; Pinna, G. 5α-reductase type i expression is downregulated in the prefrontal cortex/Brodmann’s area 9 (BA9) of depressed patients. Psychopharmacology 2014, 231, 3569–3580. [Google Scholar] [CrossRef] [PubMed]
  19. Cook, J.B.; Dumitru, A.M.; O’Buckley, T.K.; Morrow, A.L. Ethanol administration produces divergent changes in GABAergic neuroactive steroid immunohistochemistry in the rat brain. Alcohol. Clin. Exp. Res. 2014, 38, 90–99. [Google Scholar] [CrossRef] [PubMed]
  20. Germelli, L.; Da Pozzo, E.; Giacomelli, C.; Tremolanti, C.; Marchetti, L.; Wetzel, C.H.; Barresi, E.; Taliani, S.; Da Settimo, F.; Martini, C.; et al. De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein. Int. J. Mol. Sci. 2021, 22, 3115. [Google Scholar] [CrossRef] [PubMed]
  21. Tuem, K.B.; Atey, T.M. Neuroactive Steroids: Receptor Interactions and Responses. Front. Neurol. 2017, 8, 442. [Google Scholar] [CrossRef] [PubMed]
  22. Reddy, D.S. Neurosteroids: Endogenous role in the human brain and therapeutic potentials. Prog. Brain Res. 2010, 186, 113–137. [Google Scholar] [CrossRef]
  23. Lloyd-Evans, E.; Waller-Evans, H. Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease. Essays Biochem. 2020, 64, 591–606. [Google Scholar] [CrossRef] [PubMed]
  24. Majewska, M.D. Neurosteroids: Endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog. Neurobiol. 1992, 38, 379–395. [Google Scholar] [CrossRef] [PubMed]
  25. Lambert, J.J.; Belelli, D.; Peden, D.R.; Vardy, A.W.; Peters, J.A. Neurosteroid modulation of GABAA receptors. Prog. Neurobiol. 2003, 71, 67–80. [Google Scholar] [CrossRef] [PubMed]
  26. Lambert, J.J.; Cooper, M.A.; Simmons, R.D.; Weir, C.J.; Belelli, D. Neurosteroids: Endogenous allosteric modulators of GABA(A) receptors. Psychoneuroendocrinology 2009, 34 (Suppl. S1), S48–S58. [Google Scholar] [CrossRef]
  27. Herd, M.B.; Belelli, D.; Lambert, J.J. Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors. Pharmacol. Ther. 2007, 116, 20–34. [Google Scholar] [CrossRef] [PubMed]
  28. Kokate, T.G.; Svensson, B.E.; Rogawski, M.A. Anticonvulsant activity of neurosteroids: Correlation with gamma-aminobutyric acid-evoked chloride current potentiation. J. Pharmacol. Exp. Ther. 1994, 270, 1223–1229. [Google Scholar] [PubMed]
  29. Puia, G.; Vicini, S.; Seeburg, P.H.; Costa, E. Influence of recombinant gamma-aminobutyric acid-A receptor subunit composition on the action of allosteric modulators of gamma-aminobutyric acid-gated Cl- currents. Mol. Pharmacol. 1991, 39, 691–696. [Google Scholar] [PubMed]
  30. Reddy, D.S.; Rogawski, M.A. Stress-induced deoxycorticosterone-derived neurosteroids modulate GABA(A) receptor function and seizure susceptibility. J. Neurosci. 2002, 22, 3795–3805. [Google Scholar] [CrossRef]
  31. Modgil, A.; Parakala, M.L.; Ackley, M.A.; Doherty, J.J.; Moss, S.J.; Davies, P.A. Endogenous and synthetic neuroactive steroids evoke sustained increases in the efficacy of GABAergic inhibition via a protein kinase C-dependent mechanism. Neuropharmacology 2017, 113, 314–322. [Google Scholar] [CrossRef]
  32. Stell, B.M.; Brickley, S.G.; Tang, C.Y.; Farrant, M.; Mody, I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc. Natl. Acad. Sci. USA 2003, 100, 14439–14444. [Google Scholar] [CrossRef]
  33. Pinna, G. Allopregnanolone (1938–2019): A trajectory of 80 years of outstanding scientific achievements. Neurobiol. Stress 2020, 13, 100246. [Google Scholar] [CrossRef] [PubMed]
  34. Pinna, G. Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next? Front. Endocrinol. 2020, 11, 236. [Google Scholar] [CrossRef] [PubMed]
  35. Antonoudiou, P.; Colmers, P.L.W.; Walton, N.L.; Weiss, G.L.; Smith, A.C.; Nguyen, D.P.; Lewis, M.; Quirk, M.C.; Barros, L.; Melon, L.C.; et al. Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala. Biol. Psychiatry 2022, 91, 283–293. [Google Scholar] [CrossRef] [PubMed]
  36. Balan, I.; Beattie, M.C.; O’Buckley, T.K.; Aurelian, L.; Morrow, A.L. Endogenous Neurosteroid (3⍺,5⍺)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain. Sci. Rep. 2019, 9, 1220. [Google Scholar] [CrossRef] [PubMed]
  37. Balan, I.; Aurelian, L.; Williams, K.S.; Campbell, B.; Meeker, R.B.; Morrow, A.L. Inhibition of human macrophage activation via pregnane neurosteroid interactions with toll-like receptors: Sex differences and structural requirements. Front. Immunol. 2022, 13, 940095. [Google Scholar] [CrossRef] [PubMed]
  38. Langmade, S.J.; Gale, S.E.; Frolov, A.; Mohri, I.; Suzuki, K.; Mellon, S.H.; Walkley, S.U.; Covey, D.F.; Schaffer, J.E.; Ory, D.S. Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc. Natl. Acad. Sci. USA 2006, 103, 13807–13812. [Google Scholar] [CrossRef] [PubMed]
  39. Biggio, G.; Concas, A.; Follesa, P.; Sanna, E.; Serra, M. Stress, ethanol, and neuroactive steroids. Pharmacol. Ther. 2007, 116, 140–171. [Google Scholar] [CrossRef] [PubMed]
  40. Serra, M.; Pisu, M.G.; Mostallino, M.C.; Sanna, E.; Biggio, G. Changes in neuroactive steroid content during social isolation stress modulate GABAA receptor plasticity and function. Brain Res. Rev. 2008, 57, 520–530. [Google Scholar] [CrossRef] [PubMed]
  41. Janis, G.C.; Devaud, L.L.; Mitsuyama, H.; Morrow, A.L. Effects of chronic ethanol consumption and withdrawal on the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one in male and female rats. Alcohol. Clin. Exp. Res. 1998, 22, 2055–2061. [Google Scholar] [CrossRef]
  42. Khisti, R.T.; Boyd, K.N.; Kumar, S.; Morrow, A.L. Systemic ethanol administration elevates deoxycorticosterone levels and chronic ethanol exposure attenuates this response. Brain Res. 2005, 1049, 104–111. [Google Scholar] [CrossRef]
  43. Brown, E.S.; Park, J.; Marx, C.E.; Hynan, L.S.; Gardner, C.; Davila, D.; Nakamura, A.; Sunderajan, P.; Lo, A.; Holmes, T. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology 2014, 39, 2867–2873. [Google Scholar] [CrossRef] [PubMed]
  44. Girdler, S.S.; Klatzkin, R. Neurosteroids in the context of stress: Implications for depressive disorders. Pharmacol. Ther. 2007, 116, 125–139. [Google Scholar] [CrossRef] [PubMed]
  45. Osuji, I.J.; Vera-Bolanos, E.; Carmody, T.J.; Brown, E.S. Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Res. 2010, 178, 309–312. [Google Scholar] [CrossRef]
  46. Girdler, S.S.; Lindgren, M.; Porcu, P.; Rubinow, D.R.; Johnson, J.L.; Morrow, A.L. A history of depression in women is associated with an altered GABAergic neuroactive steroid profile. Psychoneuroendocrinology 2012, 37, 543–553. [Google Scholar] [CrossRef] [PubMed]
  47. Romeo, E.; Brancati, A.; De Lorenzo, A.; Fucci, P.; Furnari, C.; Pompili, E.; Sasso, G.F.; Spalletta, G.; Troisi, A.; Pasini, A. Marked decrease of plasma neuroactive steroids during alcohol withdrawal. Clin. Neuropharmacol. 1996, 19, 366–369. [Google Scholar] [CrossRef] [PubMed]
  48. Besheer, J.; Lindsay, T.G.; O’Buckley, T.K.; Hodge, C.W.; Morrow, A.L. Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring P rats. Alcohol. Clin. Exp. Res. 2010, 34, 2044–2052. [Google Scholar] [CrossRef] [PubMed]
  49. Cook, J.B.; Werner, D.F.; Maldonado-Devincci, A.M.; Leonard, M.N.; Fisher, K.R.; O’Buckley, T.K.; Porcu, P.; McCown, T.J.; Besheer, J.; Hodge, C.W.; et al. Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3alpha,5alpha-THP and reduces long-term operant ethanol self-administration. J. Neurosci. 2014, 34, 5824–5834. [Google Scholar] [CrossRef] [PubMed]
  50. Ornelas, L.C.; Boero, G.; Van Voorhies, K.; O’Buckley, T.K.; Besheer, J.; Morrow, A.L. Pharmacological administration of 3alpha,5alpha-THP into the nucleus accumbens core increases 3alpha,5alpha-THP expression and reduces alcohol self-administration. Alcohol 2023, 47, 459–469. [Google Scholar] [CrossRef]
  51. Porcu, P.; Barron, A.M.; Frye, C.A.; Walf, A.A.; Yang, S.Y.; He, X.Y.; Morrow, A.L.; Panzica, G.C.; Melcangi, R.C. Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research. J. Neuroendocrinol. 2016, 28, 12351. [Google Scholar] [CrossRef]
  52. He, J.; Evans, C.O.; Hoffman, S.W.; Oyesiku, N.M.; Stein, D.G. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp. Neurol. 2004, 189, 404–412. [Google Scholar] [CrossRef]
  53. He, J.; Hoffman, S.W.; Stein, D.G. Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury. Restor. Neurol. Neurosci. 2004, 22, 19–31. [Google Scholar] [PubMed]
  54. Noorbakhsh, F.; Baker, G.B.; Power, C. Allopregnanolone and neuroinflammation: A focus on multiple sclerosis. Front. Cell. Neurosci. 2014, 8, 134. [Google Scholar] [CrossRef] [PubMed]
  55. Schumacher, M.; Guennoun, R.; Stein, D.G.; De Nicola, A.F. Progesterone: Therapeutic opportunities for neuroprotection and myelin repair. Pharmacol. Ther. 2007, 116, 77–106. [Google Scholar] [CrossRef] [PubMed]
  56. Brinton, R.D. Neurosteroids as regenerative agents in the brain: Therapeutic implications. Nat. Rev. Endocrinol. 2013, 9, 241–250. [Google Scholar] [CrossRef] [PubMed]
  57. Wright, D.W.; Kellermann, A.L.; Hertzberg, V.S.; Clark, P.L.; Frankel, M.; Goldstein, F.C.; Salomone, J.P.; Dent, L.L.; Harris, O.A.; Ander, D.S.; et al. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann. Emerg. Med. 2007, 49, 391–402.e2. [Google Scholar] [CrossRef] [PubMed]
  58. Fox, H.C.; Sofuoglu, M.; Morgan, P.T.; Tuit, K.L.; Sinha, R. The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: Impact of gender and cue type. Psychoneuroendocrinology 2013, 38, 1532–1544. [Google Scholar] [CrossRef] [PubMed]
  59. Milivojevic, V.; Covault, J.; Angarita, G.A.; Siedlarz, K.; Sinha, R. Neuroactive steroid levels and cocaine use chronicity in men and women with cocaine use disorder receiving progesterone or placebo. Am. J. Addict. 2019, 28, 16–21. [Google Scholar] [CrossRef] [PubMed]
  60. Milivojevic, V.; Fox, H.C.; Sofuoglu, M.; Covault, J.; Sinha, R. Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women. Psychoneuroendocrinology 2016, 65, 44–53. [Google Scholar] [CrossRef] [PubMed]
  61. Milivojevic, V.; Sullivan, L.; Tiber, J.; Fogelman, N.; Simpson, C.; Hermes, G.; Sinha, R. Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder. Psychopharmacology 2023, 240, 101–114. [Google Scholar] [CrossRef]
  62. Meltzer-Brody, S.; Colquhoun, H.; Riesenberg, R.; Epperson, C.N.; Deligiannidis, K.M.; Rubinow, D.R.; Li, H.; Sankoh, A.J.; Clemson, C.; Schacterle, A.; et al. Brexanolone injection in post-partum depression: Two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018, 392, 1058–1070. [Google Scholar] [CrossRef]
  63. Kanes, S.; Colquhoun, H.; Gunduz-Bruce, H.; Raines, S.; Arnold, R.; Schacterle, A.; Doherty, J.; Epperson, C.N.; Deligiannidis, K.M.; Riesenberg, R.; et al. Brexanolone (SAGE-547 injection) in post-partum depression: A randomised controlled trial. Lancet 2017, 390, 480–489. [Google Scholar] [CrossRef] [PubMed]
  64. Balan, I.; Patterson, R.; Boero, G.; Krohn, H.; O’Buckley, T.K.; Meltzer-Brody, S.; Morrow, A.L. Brexanolone therapeutics in post-partum depression involves inhibition of systemic inflammatory pathways. eBioMedicine 2023, 89, 104473. [Google Scholar] [CrossRef] [PubMed]
  65. Patterson, R.; Krohn, H.; Richardson, E.; Kimmel, M.; Meltzer-Brody, S. A Brexanolone Treatment Program at an Academic Medical Center: Patient Selection, 90-Day Posttreatment Outcomes, and Lessons Learned. J. Acad. Consult. Liaison Psychiatry 2022, 63, 14–22. [Google Scholar] [CrossRef] [PubMed]
  66. Haney, M.; Vallée, M.; Fabre, S.; Collins Reed, S.; Zanese, M.; Campistron, G.; Arout, C.A.; Foltin, R.W.; Cooper, Z.D.; Kearney-Ramos, T.; et al. Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: Phase 1 and phase 2a randomized trials. Nat. Med. 2023, 29, 1487–1499. [Google Scholar] [CrossRef] [PubMed]
  67. Balan, I.; Aurelian, L.; Schleicher, R.; Boero, G.; O’Buckley, T.; Morrow, A.L. Neurosteroid allopregnanolone (3alpha,5alpha-THP) inhibits inflammatory signals induced by activated MyD88-dependent toll-like receptors. Transl. Psychiatry 2021, 11, 145. [Google Scholar] [CrossRef] [PubMed]
  68. Murugan, S.; Jakka, P.; Namani, S.; Mujumdar, V.; Radhakrishnan, G. The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation. J. Biol. Chem. 2019, 294, 4596–4607. [Google Scholar] [CrossRef] [PubMed]
  69. Su, L.; Sun, Y.; Ma, F.; Lü, P.; Huang, H.; Zhou, J. Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-kappaB activation and enhancing SOCS1 expression. Immunol. Lett. 2009, 125, 151–155. [Google Scholar] [CrossRef] [PubMed]
  70. Jones, L.A.; Anthony, J.P.; Henriquez, F.L.; Lyons, R.E.; Nickdel, M.B.; Carter, K.C.; Alexander, J.; Roberts, C.W. Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors. Immunology 2008, 125, 59–69. [Google Scholar] [CrossRef] [PubMed]
  71. Zhu, Y.; Wu, M.; Wu, C.Y.; Xia, G.Q. Role of progesterone in TLR4-MyD88-dependent signaling pathway in pre-eclampsia. J. Huazhong Univ. Sci. Technol. Med. Sci. 2013, 33, 730–734. [Google Scholar] [CrossRef]
  72. Zandieh, Z.; Amjadi, F.; Ashrafi, M.; Aflatoonian, A.; Fazeli, A.; Aflatoonian, R. The Effect of Estradiol and Progesterone on Toll Like Receptor Gene Expression in A Human Fallopian Tube Epithelial Cell Line. Cell J. 2016, 17, 678–691. [Google Scholar] [CrossRef]
  73. Foust-Wright, C.E.; Pulliam, S.J.; Batalden, R.P.; Berk, T.K.; Weinstein, M.M.; Wakamatsu, M.M.; Phillippe, M. Hormone Modulation of Toll-Like Receptor 5 in Cultured Human Bladder Epithelial Cells. Reprod. Sci. 2017, 24, 713–719. [Google Scholar] [CrossRef]
  74. Chen, G.; Shi, J.; Jin, W.; Wang, L.; Xie, W.; Sun, J.; Hang, C. Progesterone administration modulates TLRs/NF-kappaB signaling pathway in rat brain after cortical contusion. Ann. Clin. Lab. Sci. 2008, 38, 65–74. [Google Scholar]
  75. Tajalli-Nezhad, S.; Karimian, M.; Beyer, C.; Atlasi, M.A.; Azami Tameh, A. The regulatory role of Toll-like receptors after ischemic stroke: Neurosteroids as TLR modulators with the focus on TLR2/4. Cell Mol. Life Sci. 2019, 76, 523–537. [Google Scholar] [CrossRef] [PubMed]
  76. Patterson, R.; Balan, I.; Morrow, A.L.; Meltzer-Brody, S. Novel neurosteroid therapeutics for post-partum depression: Perspectives on clinical trials, program development, active research, and future directions. Neuropsychopharmacology 2024, 49, 67–72. [Google Scholar] [CrossRef]
  77. Naert, G.; Maurice, T.; Tapia-Arancibia, L.; Givalois, L. Neuroactive steroids modulate HPA axis activity and cerebral brain-derived neurotrophic factor (BDNF) protein levels in adult male rats. Psychoneuroendocrinology 2007, 32, 1062–1078. [Google Scholar] [CrossRef]
  78. Nin, M.S.; Martinez, L.A.; Pibiri, F.; Nelson, M.; Pinna, G. Neurosteroids reduce social isolation-induced behavioral deficits: A proposed link with neurosteroid-mediated upregulation of BDNF expression. Front. Endocrinol. 2011, 2, 73. [Google Scholar] [CrossRef] [PubMed]
  79. Almeida, F.B.; Nin, M.S.; Barros, H.M.T. The role of allopregnanolone in depressive-like behaviors: Focus on neurotrophic proteins. Neurobiol. Stress 2020, 12, 100218. [Google Scholar] [CrossRef]
  80. Balan, I.; Grusca, A.; O’Buckley, T.K.; Morrow, A.L. Neurosteroid [3α,5α]-3-hydroxy-pregnan-20-one enhances IL-10 production via endosomal TRIF-dependent TLR4 signaling pathway. Front. Endocrinol. 2023, 14, 1299420. [Google Scholar] [CrossRef] [PubMed]
  81. Hernandez, G.D.; Brinton, R.D. Allopregnanolone: Regenerative therapeutic to restore neurological health. Neurobiol. Stress 2022, 21, 100502. [Google Scholar] [CrossRef]
  82. Irwin, R.W.; Brinton, R.D. Allopregnanolone as regenerative therapeutic for Alzheimer’s disease: Translational development and clinical promise. Prog. Neurobiol. 2014, 113, 40–55. [Google Scholar] [CrossRef]
  83. Lima Giacobbo, B.; Doorduin, J.; Klein, H.C.; Dierckx, R.; Bromberg, E.; de Vries, E.F.J. Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation. Mol. Neurobiol. 2019, 56, 3295–3312. [Google Scholar] [CrossRef]
  84. Frye, C.A.; Koonce, C.J.; Edinger, K.L.; Osborne, D.M.; Walf, A.A. Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice. Horm. Behav. 2008, 54, 726–734. [Google Scholar] [CrossRef]
  85. Asselmann, E.; Kische, H.; Haring, R.; Hertel, J.; Schmidt, C.-O.; Nauck, M.; Beesdo-Baum, K.; Grabe, H.-J.; Pané-Farré, C.A. Prospective associations of androgens and sex hormone-binding globulin with 12-month, lifetime and incident anxiety and depressive disorders in men and women from the general population. J. Affect. Disord. 2019, 245, 905–911. [Google Scholar] [CrossRef] [PubMed]
  86. Kische, H.; Pieper, L.; Venz, J.; Klotsche, J.; März, W.; Koch-Gromus, U.; Pittrow, D.; Lehnert, H.; Silber, S.; Stalla, G.K.; et al. Longitudinal change instead of baseline testosterone predicts depressive symptoms. Psychoneuroendocrinology 2018, 89, 7–12. [Google Scholar] [CrossRef]
  87. Frye, C.A.; Edinger, K.; Sumida, K. Androgen Administration to Aged Male Mice Increases Anti-Anxiety Behavior and Enhances Cognitive Performance. Neuropsychopharmacology 2008, 33, 1049–1061. [Google Scholar] [CrossRef]
  88. Cai, Z.; Li, H. An Updated Review: Androgens and Cognitive Impairment in Older Men. Front. Endocrinol. 2020, 11, 586909. [Google Scholar] [CrossRef]
  89. Zuloaga, D.G.; Heck, A.L.; De Guzman, R.M.; Handa, R.J. Roles for androgens in mediating the sex differences of neuroendocrine and behavioral stress responses. Biol. Sex Differ. 2020, 11, 44. [Google Scholar] [CrossRef] [PubMed]
  90. Maninger, N.; Wolkowitz, O.M.; Reus, V.I.; Epel, E.S.; Mellon, S.H. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front. Neuroendocrinol. 2009, 30, 65–91. [Google Scholar] [CrossRef] [PubMed]
  91. Pluchino, N.; Drakopoulos, P.; Bianchi-Demicheli, F.; Wenger, J.M.; Petignat, P.; Genazzani, A.R. Neurobiology of DHEA and effects on sexuality, mood and cognition. J. Steroid Biochem. Mol. Biol. 2015, 145, 273–280. [Google Scholar] [CrossRef]
  92. Nenezic, N.; Kostic, S.; Strac, D.S.; Grunauer, M.; Nenezic, D.; Radosavljevic, M.; Jancic, J.; Samardzic, J. Dehydroepiandrosterone (DHEA): Pharmacological Effects and Potential Therapeutic Application. Mini Rev. Med. Chem. 2023, 23, 941–952. [Google Scholar] [CrossRef]
  93. Sripada, R.K.; Marx, C.E.; King, A.P.; Rajaram, N.; Garfinkel, S.N.; Abelson, J.L.; Liberzon, I. DHEA enhances emotion regulation neurocircuits and modulates memory for emotional stimuli. Neuropsychopharmacology 2013, 38, 1798–1807. [Google Scholar] [CrossRef] [PubMed]
  94. Tracey, A.Q.; Stephen, R.R.; David, W. Chapter 3—Dehydroepiandrosterone (DHEA) and DHEA Sulfate: Roles in Brain Function and Disease. In Sex Hormones in Neurodegenerative Processes and Diseases; Gorazd, D., Ed.; IntechOpen: Rijeka, Croatia, 2018. [Google Scholar]
  95. do Vale, S.; Selinger, L.; Martins, J.M.; Bicho, M.; do Carmo, I.; Escera, C. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) and emotional processing—A behavioral and electrophysiological approach. Horm. Behav. 2015, 73, 94–103. [Google Scholar] [CrossRef] [PubMed]
  96. Faviana, P.; Boldrini, L.; Gronchi, L.; Galli, L.; Erba, P.; Gentile, C.; Lippolis, P.V.; Marchetti, E.; Di Stefano, I.; Sammarco, E.; et al. Steroid Hormones as Modulators of Emotional Regulation in Male Urogenital Cancers. Int. J. Behav. Med. 2023, 30, 836–848. [Google Scholar] [CrossRef] [PubMed]
  97. Lapchak, P.A.; Chapman, D.F.; Nunez, S.Y.; Zivin, J.A. Dehydroepiandrosterone Sulfate Is Neuroprotective in a Reversible Spinal Cord Ischemia Model. Stroke 2000, 31, 1953–1957. [Google Scholar] [CrossRef] [PubMed]
  98. Vuksan-Ćusa, B.; Šagud, M.; Radoš, I. The role of dehydroepiandrosterone (DHEA) in schizophrenia. Psychiatr. Danub. 2016, 28, 30–33. [Google Scholar] [PubMed]
  99. Schmidt, P.J.; Daly, R.C.; Bloch, M.; Smith, M.J.; Danaceau, M.A.; Clair, S.L.L.; Murphy, J.H.; Haq, N.; Rubinow, D.R. Dehydroepiandrosterone Monotherapy in Midlife-Onset Major and Minor Depression. Arch. Gen. Psychiatry 2005, 62, 154–162. [Google Scholar] [CrossRef] [PubMed]
  100. Frye, C.A.; Edinger, K.L.; Lephart, E.D.; Walf, A.A. 3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats. Front. Aging Neurosci. 2010, 2, 15. [Google Scholar] [CrossRef]
  101. Brinton, R.D.; Tran, J.; Proffitt, P.; Montoya, M. 17 β-Estradiol Enhances the Outgrowth and Survival of Neocortical Neurons in Culture. Neurochem. Res. 1997, 22, 1339–1351. [Google Scholar] [CrossRef] [PubMed]
  102. Lorenzo, A.; Díaz, H.; Carrer, H.; Cáceres, A. Amygdala neurons in vitro: Neurite growth and effects of estradiol. J. Neurosci. Res. 1992, 33, 418–435. [Google Scholar] [CrossRef]
  103. McCarthy, M.M. Estradiol and the developing brain. Physiol. Rev. 2008, 88, 91–124. [Google Scholar] [CrossRef]
  104. Bustamante-Barrientos, F.A.; Méndez-Ruette, M.; Ortloff, A.; Luz-Crawford, P.; Rivera, F.J.; Figueroa, C.D.; Molina, L.; Bátiz, L.F. The Impact of Estrogen and Estrogen-Like Molecules in Neurogenesis and Neurodegeneration: Beneficial or Harmful? Front. Cell. Neurosci. 2021, 15, 636176. [Google Scholar] [CrossRef] [PubMed]
  105. Nerattini, M.; Jett, S.; Andy, C.; Carlton, C.; Zarate, C.; Boneu, C.; Battista, M.; Pahlajani, S.; Loeb-Zeitlin, S.; Havryulik, Y.; et al. Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer’s disease and dementia. Front. Aging Neurosci. 2023, 15, 1260427. [Google Scholar] [CrossRef]
  106. Abbas, N.A.T.; Hassan, H.A. The protective and therapeutic effects of 5-androstene3β, 17β-diol (ADIOL) in abdominal post-operative adhesions in rat: Suppressing TLR4/NFκB/HMGB1/TGF1 β/α SMA pathway. Int. Immunopharmacol. 2022, 109, 108801. [Google Scholar] [CrossRef] [PubMed]
  107. Iwasaki, Y.; Asai, M.; Yoshida, M.; Nigawara, T.; Kambayashi, M.; Nakashima, N. Dehydroepiandrosterone-Sulfate Inhibits Nuclear Factor-κB-Dependent Transcription in Hepatocytes, Possibly through Antioxidant Effect. J. Clin. Endocrinol. Metab. 2004, 89, 3449–3454. [Google Scholar] [CrossRef]
  108. Saijo, K.; Collier, J.G.; Li, A.C.; Katzenellenbogen, J.A.; Glass, C.K. An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 2011, 145, 584–595. [Google Scholar] [CrossRef]
  109. Alexaki, V.I.; Fodelianaki, G.; Neuwirth, A.; Mund, C.; Kourgiantaki, A.; Ieronimaki, E.; Lyroni, K.; Troullinaki, M.; Fujii, C.; Kanczkowski, W.; et al. DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway. Mol. Psychiatry 2018, 23, 1410–1420. [Google Scholar] [CrossRef] [PubMed]
  110. Yilmaz, C.; Karali, K.; Fodelianaki, G.; Gravanis, A.; Chavakis, T.; Charalampopoulos, I.; Alexaki, V.I. Neurosteroids as regulators of neuroinflammation. Front. Neuroendocrinol. 2019, 55, 100788. [Google Scholar] [CrossRef]
  111. Cao, J.; Yu, L.; Zhao, J.; Ma, H. Effect of dehydroepiandrosterone on the immune function of mice in vivo and in vitro. Mol. Immunol. 2019, 112, 283–290. [Google Scholar] [CrossRef]
  112. Cao, J.; Li, Q.; Shen, X.; Yao, Y.; Li, L.; Ma, H. Dehydroepiandrosterone attenuates LPS-induced inflammatory responses via activation of Nrf2 in RAW264.7 macrophages. Mol. Immunol. 2021, 131, 97–111. [Google Scholar] [CrossRef]
  113. Zhao, J.; Cao, J.; Yu, L.; Ma, H. Dehydroepiandrosterone alleviates E. Coli O157:H7-induced inflammation by preventing the activation of p38 MAPK and NF-kappaB pathways in mice peritoneal macrophages. Mol. Immunol. 2019, 114, 114–122. [Google Scholar] [CrossRef]
  114. Zhao, J.; Cao, J.; Yu, L.; Ma, H. Dehydroepiandrosterone resisted E. Coli O157:H7-induced inflammation via blocking the activation of p38 MAPK and NF-kappaB pathways in mice. Cytokine 2020, 127, 154955. [Google Scholar] [CrossRef] [PubMed]
  115. Spence, R.D.; Voskuhl, R.R. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front. Neuroendocrinol. 2012, 33, 105–115. [Google Scholar] [CrossRef]
  116. Vegeto, E.; Pollio, G.; Ciana, P.; Maggi, A. Estrogen blocks inducible nitric oxide synthase accumulation in LPS-activated microglia cells. Exp. Gerontol. 2000, 35, 1309–1316. [Google Scholar] [CrossRef] [PubMed]
  117. Vegeto, E.; Belcredito, S.; Etteri, S.; Ghisletti, S.; Brusadelli, A.; Meda, C.; Krust, A.; Dupont, S.; Ciana, P.; Chambon, P.; et al. Estrogen receptor-alpha mediates the brain antiinflammatory activity of estradiol. Proc. Natl. Acad. Sci. USA 2003, 100, 9614–9619. [Google Scholar] [CrossRef] [PubMed]
  118. Vegeto, E.; Belcredito, S.; Ghisletti, S.; Meda, C.; Etteri, S.; Maggi, A. The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation. Endocrinology 2006, 147, 2263–2272. [Google Scholar] [CrossRef] [PubMed]
  119. Vegeto, E.; Villa, A.; Della Torre, S.; Crippa, V.; Rusmini, P.; Cristofani, R.; Galbiati, M.; Maggi, A.; Poletti, A. The Role of Sex and Sex Hormones in Neurodegenerative Diseases. Endocr. Rev. 2020, 41, 273–319. [Google Scholar] [CrossRef]
  120. Czlonkowska, A.; Ciesielska, A.; Gromadzka, G.; Kurkowska-Jastrzebska, I. Estrogen and cytokines production—The possible cause of gender differences in neurological diseases. Curr. Pharm. Des. 2005, 11, 1017–1030. [Google Scholar] [CrossRef]
  121. Villa, A.; Vegeto, E.; Poletti, A.; Maggi, A. Estrogens, Neuroinflammation, and Neurodegeneration. Endocr. Rev. 2016, 37, 372–402. [Google Scholar] [CrossRef]
  122. Villa, A.; Rizzi, N.; Vegeto, E.; Ciana, P.; Maggi, A. Estrogen accelerates the resolution of inflammation in macrophagic cells. Sci. Rep. 2015, 5, 15224. [Google Scholar] [CrossRef]
  123. Siani, F.; Greco, R.; Levandis, G.; Ghezzi, C.; Daviddi, F.; Demartini, C.; Vegeto, E.; Fuzzati-Armentero, M.T.; Blandini, F. Influence of Estrogen Modulation on Glia Activation in a Murine Model of Parkinson’s Disease. Front. Neurosci. 2017, 11, 306. [Google Scholar] [CrossRef]
  124. Heitzer, M.; Kaiser, S.; Kanagaratnam, M.; Zendedel, A.; Hartmann, P.; Beyer, C.; Johann, S. Administration of 17beta-Estradiol Improves Motoneuron Survival and Down-regulates Inflammasome Activation in Male SOD1(G93A) ALS Mice. Mol. Neurobiol. 2017, 54, 8429–8443. [Google Scholar] [CrossRef] [PubMed]
  125. Traish, A.; Bolanos, J.; Nair, S.; Saad, F.; Morgentaler, A. Do Androgens Modulate the Pathophysiological Pathways of Inflammation? Appraising the Contemporary Evidence. J. Clin. Med. 2018, 7, 549. [Google Scholar] [CrossRef]
  126. Zahaf, A.; Kassoussi, A.; Hutteau-Hamel, T.; Mellouk, A.; Marie, C.; Zoupi, L.; Tsouki, F.; Mattern, C.; Bobé, P.; Schumacher, M.; et al. Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination. Nat. Commun. 2023, 14, 1592. [Google Scholar] [CrossRef]
  127. Vancolen, S.; Sebire, G.; Robaire, B. Influence of androgens on the innate immune system. Andrology 2023, 11, 1237–1244. [Google Scholar] [CrossRef] [PubMed]
  128. Stein, B.; Yang, M.X. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol. Cell. Biol. 1995, 15, 4971–4979. [Google Scholar] [CrossRef]
  129. Kettelhut, A.; Bowman, E.; Gabriel, J.; Hand, B.; Liyanage, N.P.M.; Kulkarni, M.; Avila-Soto, F.; Lake, J.E.; Funderburg, N.T. Estrogen May Enhance Toll-Like Receptor 4-Induced Inflammatory Pathways in People with HIV: Implications for Transgender Women on Hormone Therapy. Front. Immunol. 2022, 13, 879600. [Google Scholar] [CrossRef]
  130. Young, N.A.; Wu, L.C.; Burd, C.J.; Friedman, A.K.; Kaffenberger, B.H.; Rajaram, M.V.; Schlesinger, L.S.; James, H.; Shupnik, M.A.; Jarjour, W.N. Estrogen modulation of endosome-associated toll-like receptor 8: An IFNalpha-independent mechanism of sex-bias in systemic lupus erythematosus. Clin. Immunol. 2014, 151, 66–77. [Google Scholar] [CrossRef] [PubMed]
  131. Zandieh, Z.; Amjadi, F.; Vakilian, H.; Aflatoonian, K.; Amirchaghmaghi, E.; Fazeli, A.; Aflatoonian, R. Sex hormones alter the response of Toll-like receptor 3 to its specific ligand in fallopian tube epithelial cells. Clin. Exp. Reprod. Med. 2018, 45, 154–162. [Google Scholar] [CrossRef]
  132. Calippe, B.; Douin-Echinard, V.; Laffargue, M.; Laurell, H.; Rana-Poussine, V.; Pipy, B.; Guéry, J.C.; Bayard, F.; Arnal, J.F.; Gourdy, P. Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: Involvement of the phosphatidylinositol 3-kinase pathway. J. Immunol. 2008, 180, 7980–7988. [Google Scholar] [CrossRef]
  133. Calippe, B.; Douin-Echinard, V.; Delpy, L.; Laffargue, M.; Lélu, K.; Krust, A.; Pipy, B.; Bayard, F.; Arnal, J.F.; Guéry, J.C.; et al. 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J. Immunol. 2010, 185, 1169–1176. [Google Scholar] [CrossRef]
  134. Brauer, V.S.; Zambuzi, F.A.; Espíndola, M.S.; Cavalcanti Neto, M.P.; Prado, M.K.B.; Cardoso, P.M.; Soares, L.S.; Galvao-Lima, L.J.; Leopoldino, A.M.; Cardoso, C.R.d.B.; et al. The influence of dehydroepiandrosterone on effector functions of neutrophils. Braz. J. Pharm. Sci. 2021, 57, e19139. [Google Scholar] [CrossRef]
  135. Rettew, J.A.; Huet-Hudson, Y.M.; Marriott, I. Testosterone Reduces Macrophage Expression in the Mouse of Toll-Like Receptor 4, a Trigger for Inflammation and Innate Immunity. Biol. Reprod. 2008, 78, 432–437. [Google Scholar] [CrossRef]
  136. Al-Quraishy, S.; Dkhil, M.A.; S Abdel-Baki, A.-A.; Araúzo-Bravo, M.J.; Delic, D.; Wunderlich, F. Testosterone persistently dysregulates hepatic expression of Tlr6 and Tlr8 induced by Plasmodium chabaudi malaria. Parasitol. Res. 2014, 113, 3609–3620. [Google Scholar] [CrossRef]
  137. Buendía-González, F.O.; Legorreta-Herrera, M. The Similarities and Differences between the Effects of Testosterone and DHEA on the Innate and Adaptive Immune Response. Biomolecules 2022, 12, 1768. [Google Scholar] [CrossRef]
  138. Matsuda, A.; Furukawa, K.; Suzuki, H.; Matsutani, T.; Tajiri, T.; Chaudry, I.H. Dehydroepiandrosterone Modulates Toll-Like Receptor Expression on Splenic Macrophages of Mice after Severe Polymicrobial Sepsis. Shock 2005, 24, 364–369. [Google Scholar] [CrossRef]
  139. Takeda, K.; Kaisho, T.; Akira, S. Toll-Like Receptors. Annu. Rev. Immunol. 2003, 21, 335–376. [Google Scholar] [CrossRef]
  140. Gay, N.J.; Symmons, M.F.; Gangloff, M.; Bryant, C.E. Assembly and localization of Toll-like receptor signalling complexes. Nat. Rev. Immunol. 2014, 14, 546–558. [Google Scholar] [CrossRef]
  141. Kawasaki, T.; Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 2014, 5, 461. [Google Scholar] [CrossRef]
  142. Akira, S.; Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 2004, 4, 499–511. [Google Scholar] [CrossRef]
  143. Hanke, M.L.; Kielian, T. Toll-like receptors in health and disease in the brain: Mechanisms and therapeutic potential. Clin. Sci. 2011, 121, 367–387. [Google Scholar] [CrossRef]
  144. Esen, N.; Kielian, T. Toll-Like Receptors in Brain Abscess. In Toll-like Receptors: Roles in Infection and Neuropathology; Kielian, T., Ed.; Springer: Berlin/Heidelberg, Germany, 2009; pp. 41–61. [Google Scholar]
  145. Airapetov, M.I.; Eresko, S.O.; Lebedev, A.A.; Bychkov, E.R.; Shabanov, P.D. The Role of Toll-Like Receptors in Neuroimmunology of Alcoholism. Biochem. Suppl. Ser. B Biomed. Chem. 2021, 15, 71–79. [Google Scholar] [CrossRef]
  146. Aurelian, L.; Balan, I. GABAAR α2-activated neuroimmune signal controls binge drinking and impulsivity through regulation of the CCL2/CX3CL1 balance. Psychopharmacology 2019, 236, 3023–3043. [Google Scholar] [CrossRef]
  147. Balan, I.; Warnock, K.T.; Puche, A.; Gondre-Lewis, M.C.; June, H.; Aurelian, L. The GABAA Receptor α2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse. Brain Sci. 2018, 8, 72. [Google Scholar] [CrossRef] [PubMed]
  148. Balan, I.; Warnock, K.T.; Puche, A.; Gondre-Lewis, M.C.; Aurelian, L. Innately activated TLR4 signal in the nucleus accumbens is sustained by CRF amplification loop and regulates impulsivity. Brain Behav. Immun. 2018, 69, 139–153. [Google Scholar] [CrossRef] [PubMed]
  149. Gao, W.; Xiong, Y.; Li, Q.; Yang, H. Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics. Front. Physiol. 2017, 8, 508. [Google Scholar] [CrossRef]
  150. Xie, J.; Van Hoecke, L.; Vandenbroucke, R.E. The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology. Front. Immunol. 2021, 12, 796867. [Google Scholar] [CrossRef]
  151. Li, T.; Chen, H.; Xu, B.; Yu, M.; Li, J.; Shi, Y.; Xia, S.; Wu, S. Deciphering the interplay between LPS/TLR4 pathways, neurotransmitter, and deltamethrin-induced depressive-like behavior: Perspectives from the gut-brain axis. Pestic. Biochem. Physiol. 2023, 197, 105697. [Google Scholar] [CrossRef]
  152. Liu, J.; Buisman-Pijlman, F.; Hutchinson, M.R. Toll-like receptor 4: Innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder. Front. Neurosci. 2014, 8, 309. [Google Scholar] [CrossRef]
  153. Figueroa-Hall, L.K.; Paulus, M.P.; Savitz, J. Toll-Like Receptor Signaling in Depression. Psychoneuroendocrinology 2020, 121, 104843. [Google Scholar] [CrossRef]
  154. Du, Y.; Yan, T.; Wu, B.; He, B.; Jia, Y. Research on the mechanism of antidepressive effect of Suanzaoren Decoction through TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway. J. Ethnopharmacol. 2024, 319, 117190. [Google Scholar] [CrossRef]
  155. An, Q.; Xia, J.; Pu, F.; Shi, S. MCPIP1 alleviates depressive-like behaviors in mice by inhibiting the TLR4/TRAF6/NF-κB pathway to suppress neuroinflammation. Mol. Med. Rep. 2024, 29, 6. [Google Scholar] [CrossRef] [PubMed]
  156. Souza-Junior, F.J.C.; Cunha, L.C.; Lisboa, S.F. Toll-like receptor 4 in the interface between neuroimmune response and behavioral alterations caused by stress. Explor. Neuroprot. Ther. 2022, 2, 182–209. [Google Scholar] [CrossRef]
  157. Crews, F.T.; Walter, T.J.; Coleman, L.G., Jr.; Vetreno, R.P. Toll-like receptor signaling and stages of addiction. Psychopharmacology 2017, 234, 1483–1498. [Google Scholar] [CrossRef] [PubMed]
  158. Crews, F.T.; Lawrimore, C.J.; Walter, T.J.; Coleman, L.G., Jr. The role of neuroimmune signaling in alcoholism. Neuropharmacology 2017, 122, 56–73. [Google Scholar] [CrossRef] [PubMed]
  159. Coleman, L.G., Jr.; Zou, J.; Crews, F.T. Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J. Neuroinflammation 2017, 14, 22. [Google Scholar] [CrossRef] [PubMed]
  160. Vetreno, R.P.; Qin, L.; Coleman, L.G., Jr.; Crews, F.T. Increased Toll-like Receptor-MyD88-NFkappaB-Proinflammatory neuroimmune signaling in the orbitofrontal cortex of humans with alcohol use disorder. Alcohol. Clin. Exp. Res. 2021, 45, 1747–1761. [Google Scholar] [CrossRef] [PubMed]
  161. Liu, J.; Yang, A.R.; Kelly, T.; Puche, A.; Esoga, C.; June, H.L., Jr.; Elnabawi, A.; Merchenthaler, I.; Sieghart, W.; June, H.L., Sr.; et al. Binge alcohol drinking is associated with GABAA alpha2-regulated Toll-like receptor 4 (TLR4) expression in the central amygdala. Proc. Natl. Acad. Sci. USA 2011, 108, 4465–4470. [Google Scholar] [CrossRef]
  162. Czerwińska-Błaszczyk, A.; Pawlak, E.; Pawłowski, T. The Significance of Toll-Like Receptors in the Neuroimmunologic Background of Alcohol Dependence. Front. Psychiatry 2021, 12, 797123. [Google Scholar] [CrossRef] [PubMed]
  163. June, H.L.; Liu, J.; Warnock, K.T.; Bell, K.A.; Balan, I.; Bollino, D.; Puche, A.; Aurelian, L. CRF-amplified neuronal TLR4/MCP-1 signaling regulates alcohol self-administration. Neuropsychopharmacology 2015, 40, 1549–1559. [Google Scholar] [CrossRef]
  164. Lovelock, D.F.; Liu, W.; Langston, S.E.; Liu, J.; Van Voorhies, K.; Giffin, K.A.; Vetreno, R.P.; Crews, F.T.; Besheer, J. The Toll-like receptor 7 agonist imiquimod increases ethanol self-administration and induces expression of Toll-like receptor related genes. Addict. Biol. 2022, 27, e13176. [Google Scholar] [CrossRef]
  165. Aurelian, L.; Warnock, K.T.; Balan, I.; Puche, A.; June, H. TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation. Transl. Psychiatry 2016, 6, e815. [Google Scholar] [CrossRef] [PubMed]
  166. Dong, X.Q.; Yu, W.H.; Hu, Y.Y.; Zhang, Z.Y.; Huang, M. Oxymatrine reduces neuronal cell apoptosis by inhibiting Toll-like receptor 4/nuclear factor kappa-B-dependent inflammatory responses in traumatic rat brain injury. Inflamm. Res. 2011, 60, 533–539. [Google Scholar] [CrossRef]
  167. Shi, H.; Hua, X.; Kong, D.; Stein, D.; Hua, F. Role of Toll-like receptor mediated signaling in traumatic brain injury. Neuropharmacology 2019, 145, 259–267. [Google Scholar] [CrossRef] [PubMed]
  168. El Baassiri, M.G.; Chun, Y.H.; Rahal, S.S.; Fulton, W.B.; Sodhi, C.P.; Hackam, D.J.; Nasr, I.W. Infiltrating anti-inflammatory monocytes modulate microglial activation through toll-like receptor 4/interferon-dependent pathways following traumatic brain injury. J. Trauma Acute Care Surg. 2023, 95, 368–375. [Google Scholar] [CrossRef] [PubMed]
  169. Okun, E.; Griffioen, K.J.; Lathia, J.D.; Tang, S.C.; Mattson, M.P.; Arumugam, T.V. Toll-like receptors in neurodegeneration. Brain Res. Rev. 2009, 59, 278–292. [Google Scholar] [CrossRef] [PubMed]
  170. Lehmann, S.M.; Kruger, C.; Park, B.; Derkow, K.; Rosenberger, K.; Baumgart, J.; Trimbuch, T.; Eom, G.; Hinz, M.; Kaul, D.; et al. An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat. Neurosci. 2012, 15, 827–835. [Google Scholar] [CrossRef]
  171. Lehnardt, S.; Lachance, C.; Patrizi, S.; Lefebvre, S.; Follett, P.L.; Jensen, F.E.; Rosenberg, P.A.; Volpe, J.J.; Vartanian, T. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J. Neurosci. 2002, 22, 2478–2486. [Google Scholar] [CrossRef] [PubMed]
  172. Lehnardt, S.; Massillon, L.; Follett, P.; Jensen, F.E.; Ratan, R.; Rosenberg, P.A.; Volpe, J.J.; Vartanian, T. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc. Natl. Acad. Sci. USA 2003, 100, 8514–8519. [Google Scholar] [CrossRef]
  173. Trotta, T.; Porro, C.; Calvello, R.; Panaro, M.A. Biological role of Toll-like receptor-4 in the brain. J. Neuroimmunol. 2014, 268, 1–12. [Google Scholar] [CrossRef]
  174. Essam, R.M.; Saadawy, M.A.; Gamal, M.; Abdelsalam, R.M.; El-Sahar, A.E. Lactoferrin averts neurological and behavioral impairments of thioacetamide-induced hepatic encephalopathy in rats via modulating HGMB1/TLR-4/MyD88/Nrf2 pathway. Neuropharmacology 2023, 236, 109575. [Google Scholar] [CrossRef]
  175. Caso, J.R.; Pradillo, J.M.; Hurtado, O.; Lorenzo, P.; Moro, M.A.; Lizasoain, I. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007, 115, 1599–1608. [Google Scholar] [CrossRef] [PubMed]
  176. Hua, F.; Ma, J.; Ha, T.; Xia, Y.; Kelley, J.; Williams, D.L.; Kao, R.L.; Browder, I.W.; Schweitzer, J.B.; Kalbfleisch, J.H.; et al. Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. J. Neuroimmunol. 2007, 190, 101–111. [Google Scholar] [CrossRef] [PubMed]
  177. Shichita, T.; Sakaguchi, R.; Suzuki, M.; Yoshimura, A. Post-ischemic inflammation in the brain. Front. Immunol. 2012, 3, 132. [Google Scholar] [CrossRef] [PubMed]
  178. Gesuete, R.; Kohama, S.G.; Stenzel-Poore, M.P. Toll-like receptors and ischemic brain injury. J. Neuropathol. Exp. Neurol. 2014, 73, 378–386. [Google Scholar] [CrossRef] [PubMed]
  179. Zhou, R.; Wu, L.; Jin, N.; Sha, S.; Ouyang, Y. L-F001, a multifunctional fasudil-lipoic acid dimer, antagonizes hypoxic-ischemic brain damage by inhibiting the TLR4/MyD88 signaling pathway. Brain Behav. 2023, 13, e3280. [Google Scholar] [CrossRef]
  180. Balaji, R.; Subbanna, M.; Shivakumar, V.; Abdul, F.; Venkatasubramanian, G.; Debnath, M. Pattern of expression of Toll like receptor (TLR)-3 and -4 genes in drug-naive and antipsychotic treated patients diagnosed with schizophrenia. Psychiatry Res. 2020, 285, 112727. [Google Scholar] [CrossRef] [PubMed]
  181. Weickert, T.W.; Ji, E.; Galletly, C.; Boerrigter, D.; Morishima, Y.; Bruggemann, J.; Balzan, R.; O’Donnell, M.; Liu, D.; Lenroot, R.; et al. Toll-Like Receptor mRNA Levels in Schizophrenia: Association with Complement Factors and Cingulate Gyrus Cortical Thinning. Schizophr. Bull. 2023, 50, 403–417. [Google Scholar] [CrossRef] [PubMed]
  182. Liu, T.; Gao, Y.J.; Ji, R.R. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci. Bull. 2012, 28, 131–144. [Google Scholar] [CrossRef]
  183. Liu, X.; Yang, W.; Zhu, C.; Sun, S.; Wu, S.; Wang, L.; Wang, Y.; Ge, Z. Toll-like receptors and their role in neuropathic pain and migraine. Mol. Brain 2022, 15, 73. [Google Scholar] [CrossRef]
  184. Nicotra, L.; Loram, L.C.; Watkins, L.R.; Hutchinson, M.R. Toll-like receptors in chronic pain. Exp. Neurol. 2012, 234, 316–329. [Google Scholar] [CrossRef]
  185. Vezzani, A.; Ruegg, S. The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized: Introduction. Epilepsia 2011, 52 (Suppl. S3), 1–4. [Google Scholar] [CrossRef] [PubMed]
  186. Maroso, M.; Balosso, S.; Ravizza, T.; Liu, J.; Bianchi, M.E.; Vezzani, A. Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: The importance of IL-1beta and high-mobility group box 1. J. Intern. Med. 2011, 270, 319–326. [Google Scholar] [CrossRef] [PubMed]
  187. Chaudhary, A.; Mehra, P.; Keshri, A.K.; Rawat, S.S.; Mishra, A.; Prasad, A. The Emerging Role of Toll-Like Receptor-Mediated Neuroinflammatory Signals in Psychiatric Disorders and Acquired Epilepsy. Mol. Neurobiol. 2024, 61, 1527–1542. [Google Scholar] [CrossRef]
  188. Purdy, R.H.; Moore, P.H.; Morrow, A.L.; Paul, S.M. The 3a-hydroxy ring-A-reduced metabolites of progesterone and deoxycorticosterone: Natural ligands of central GABAA receptors. In Neurosteroids and Brain Function; Costa, E., Paul, S.M., Eds.; Raven Press: New York, NY, USA, 1991; pp. 95–102. [Google Scholar]
  189. Corpechot, C.; Young, J.; Calvel, M.; Wehrey, C.; Veltz, J.N.; Touyer, G.; Mouren, M.; Prasad, V.V.K.; Banner, C.; Sjövall, J.; et al. Neurosteroids: 3a-hydroxy-5a-pregnan-20-one and its precursors in the brain, plasma, and steroidogenic glands of male and female rats. Endocrinology 1993, 133, 1003–1009. [Google Scholar] [CrossRef]
  190. Mensah-Nyagan, A.G.; Do-Rego, J.L.; Beaujean, D.; Luu-The, V.; Pelletier, G.; Vaudry, H. Neurosteroids: Expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol. Rev. 1999, 51, 63–81. [Google Scholar] [PubMed]
  191. Mellon, S.H.; Deschepper, C.F. Neurosteroid biosynthesis: Genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res. 1993, 629, 283–292. [Google Scholar] [CrossRef] [PubMed]
  192. Testas, I.J.; Hu, Z.Y.; Baulieuf, E.E.; Robel, P. Neurosteroids: Biosynthesis of Pregnenolone and Progesterone in Primary Cultures of Rat Glial Cells. Endocrinology 1989, 125, 2083–2091. [Google Scholar] [CrossRef] [PubMed]
  193. Papadopoulos, V.; Liu, J.; Culty, M. Is there a mitochondrial signaling complex facilitating cholesterol import? Mol. Cell. Endocrinol. 2007, 265–266, 59–64. [Google Scholar] [CrossRef] [PubMed]
  194. Reddy, D.S. Mass spectrometric assay and physiological-pharmacological activity of androgenic neurosteroids. Neurochem. Int. 2008, 52, 541–553. [Google Scholar] [CrossRef]
  195. Jellinck, P.H.; Kaufmann, M.; Gottfried-Blackmore, A.; McEwen, B.S.; Jones, G.; Bulloch, K. Selective conversion by microglia of dehydroepiandrosterone to 5-androstenediol—A steroid with inherent estrogenic properties. J. Steroid Biochem. Mol. Biol. 2007, 107, 156–162. [Google Scholar] [CrossRef]
  196. Lathe, R. Steroid and sterol 7-hydroxylation: Ancient pathways. Steroids 2002, 67, 967–977. [Google Scholar] [CrossRef] [PubMed]
  197. Strott, C.A. Sulfonation and molecular action. Endocr. Rev. 2002, 23, 703–732. [Google Scholar] [CrossRef]
  198. Le Goascogne, C.; Robel, P.; Gouézou, M.; Sananes, N.; Baulieu, E.-E.; Waterman, M. Neurosteroids: Cytochrome P-450scc in Rat Brain. Science 1987, 237, 1212–1215. [Google Scholar] [CrossRef] [PubMed]
  199. Li, P.K.; Milano, S.; Kluth, L.; Rhodes, M.E. Synthesis and sulfatase inhibitory activities of non-steroidal estrone sulfatase inhibitors. J. Steroid Biochem. Mol. Biol. 1996, 59, 41–48. [Google Scholar] [CrossRef] [PubMed]
  200. Rupprecht, R. Neuroactive steroids: Mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003, 28, 139–168. [Google Scholar] [CrossRef] [PubMed]
  201. Slater, E.P.; Hesse, H.; Beato, M. Regulation of transcription by steroid hormones. Ann. N. Y. Acad. Sci. 1994, 733, 103–112. [Google Scholar] [CrossRef] [PubMed]
  202. Vallée, M.; Vitiello, S.; Bellocchio, L.; Hébert-Chatelain, E.; Monlezun, S.; Martin-Garcia, E.; Kasanetz, F.; Baillie, G.L.; Panin, F.; Cathala, A.; et al. Pregnenolone can protect the brain from cannabis intoxication. Science 2014, 343, 94–98. [Google Scholar] [CrossRef] [PubMed]
  203. Murakami, K.; Fellous, A.; Baulieu, E.E.; Robel, P. Pregnenolone binds to microtubule-associated protein 2 and stimulates microtubule assembly. Proc. Natl. Acad. Sci. USA 2000, 97, 3579–3584. [Google Scholar] [CrossRef] [PubMed]
  204. Frye, C.A.; Koonce, C.J.; Walf, A.A. Role of pregnane xenobiotic receptor in the midbrain ventral tegmental area for estradiol- and 3alpha,5alpha-THP-facilitated lordosis of female rats. Psychopharmacology 2014, 231, 3365–3374. [Google Scholar] [CrossRef]
  205. Frye, C.A.; Koonce, C.J.; Walf, A.A. Novel receptor targets for production and action of allopregnanolone in the central nervous system: A focus on pregnane xenobiotic receptor. Front. Cell. Neurosci. 2014, 8, 106. [Google Scholar] [CrossRef]
  206. Sever, R.; Glass, C.K. Signaling by nuclear receptors. Cold Spring Harb. Perspect. Biol. 2013, 5, a016709. [Google Scholar] [CrossRef]
  207. Arnal, J.F.; Lenfant, F.; Metivier, R.; Flouriot, G.; Henrion, D.; Adlanmerini, M.; Fontaine, C.; Gourdy, P.; Chambon, P.; Katzenellenbogen, B.; et al. Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications. Physiol. Rev. 2017, 97, 1045–1087. [Google Scholar] [CrossRef]
  208. Gu, Y.; Wu, Y.; Su, W.; Xing, L.; Shen, Y.; He, X.; Li, L.; Yuan, Y.; Tang, X.; Chen, G. 17β-Estradiol Enhances Schwann Cell Differentiation via the ERβ-ERK1/2 Signaling Pathway and Promotes Remyelination in Injured Sciatic Nerves. Front. Pharmacol. 2018, 9, 1026. [Google Scholar] [CrossRef]
  209. Sieghart, W. Structure, pharmacology, and function of GABAA receptor subtypes. Adv. Pharmacol. 2006, 54, 231–263. [Google Scholar] [CrossRef]
  210. Hosie, A.M.; Wilkins, M.E.; da Silva, H.M.; Smart, T.G. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 2006, 444, 486–489. [Google Scholar] [CrossRef]
  211. Puia, G.; Ducic, I.; Vicini, S.; Costa, E. Does neurosteroid modulatory efficacy depend on GABAA receptor subunit composition? Recept. Channels 1993, 1, 135–142. [Google Scholar]
  212. Mihalek, R.M.; Banerjee, P.K.; Korpi, E.R.; Quinlan, J.J.; Firestone, L.L.; Mi, Z.P.; Lagenaur, C.; Tretter, V.; Sieghart, W.; Anagnostaras, S.G.; et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc. Natl. Acad. Sci. USA 1999, 96, 12905–12910. [Google Scholar] [CrossRef]
  213. Spigelman, I.; Li, Z.; Liang, J.; Cagetti, E.; Samzadeh, S.; Mihalek, R.M.; Homanics, G.E.; Olsen, R.W. Reduced inhibition and sensitivity to neurosteroids in hippocampus of mice lacking the GABA(A) receptor delta subunit. J. Neurophysiol. 2003, 90, 903–910. [Google Scholar] [CrossRef]
  214. Lambert, J.J.; Belelli, D.; Hill-Venning, C.; Peters, J.A. Neurosteroids and GABAA receptor function. Trends Pharmacol. Sci. 1995, 16, 295–303. [Google Scholar] [CrossRef]
  215. Purdy, R.H.; Moore, P.H.; Rao, P.N.; Hagino, N.; Yamaguchi, T.; Schmidt, P.; Rubinow, D.; Morrow, A.L.; Paul, S.M. Radioimmunoassay of 3 alpha-hydroxy-5 alpha-pregnan-20-one in rat and human plasma. Steroids 1990, 55, 290–296. [Google Scholar] [CrossRef]
  216. Majewska, M.D.; Schwartz, R.D. Pregnenolone-sulfate: An endogenous antagonist of the g-aminobutyric acid receptor complex in brain. Brain Res. 1987, 404, 355–360. [Google Scholar] [CrossRef] [PubMed]
  217. Majewska, M.D.; Demirgören, S.; London, E.D. Binding of pregnenolone sulfate to rat brain membranes suggests multiple sites of steroid action at the GABAA receptor. Eur. J. Pharmacol. Mol. Pharmacol. 1990, 189, 307–315. [Google Scholar] [CrossRef] [PubMed]
  218. Majewska, M.D.; Demirgören, S.; Spivak, C.E.; London, E.D. The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor. Brain Res. 1990, 526, 143–146. [Google Scholar] [CrossRef] [PubMed]
  219. Park-Chung, M.; Malayev, A.; Purdy, R.H.; Gibbs, T.T.; Farb, D.H. Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites. Brain Res. 1999, 830, 72–87. [Google Scholar] [CrossRef]
  220. Wu, F.S.; Gibbs, T.T.; Farb, D.H. Pregnenolone sulfate: A positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol. Pharmacol. 1991, 40, 333–336. [Google Scholar] [PubMed]
  221. Shi, S.H.; Hayashi, Y.; Petralia, R.S.; Zaman, S.H.; Wenthold, R.J.; Svoboda, K.; Malinow, R. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 1999, 284, 1811–1816. [Google Scholar] [CrossRef] [PubMed]
  222. Maurice, T.; Roman, F.J.; Privat, A. Modulation by neurosteroids of the in vivo (+)-[3H]SKF-10,047 binding to s1 receptors in the mouse forebrain. J. Neurosci. Res. 1996, 46, 734–743. [Google Scholar] [CrossRef]
  223. Reddy, D.S. Is there a physiological role for the neurosteroid THDOC in stress-sensitive conditions? Trends Pharmacol. Sci. 2003, 24, 103–106. [Google Scholar] [CrossRef] [PubMed]
  224. Schverer, M.; Lanfumey, L.; Baulieu, E.E.; Froger, N.; Villey, I. Neurosteroids: Non-genomic pathways in neuroplasticity and involvement in neurological diseases. Pharmacol. Ther. 2018, 191, 190–206. [Google Scholar] [CrossRef]
  225. Paul, S.M.; Pinna, G.; Guidotti, A. Allopregnanolone: From molecular pathophysiology to therapeutics. A historical perspective. Neurobiol. Stress 2020, 12, 100215. [Google Scholar] [CrossRef]
  226. Milivojevic, V.; Charron, L.; Fogelman, N.; Hermes, G.; Sinha, R. Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder. Biomolecules 2022, 12, 1593. [Google Scholar] [CrossRef] [PubMed]
  227. Bixo, M.; Andersson, A.; Winblad, B.; Purdy, R.H.; Backstrom, T. Progesterone, 5⍺-pregnan-3,20-dione and 3⍺-hydroxy-5⍺-pregnane-20-one in specific regions of the human female brain in different endocrine states. Brain Res. 1997, 764, 173–178. [Google Scholar] [CrossRef] [PubMed]
  228. Adinoff, B.; Junghanns, K.; Kiefer, F.; Krishnan-Sarin, S. Suppression of the HPA axis stress-response: Implications for relapse. Alcohol. Clin. Exp. Res. 2005, 29, 1351–1355. [Google Scholar] [CrossRef] [PubMed]
  229. Adinoff, B.; Krebaum, S.R.; Chandler, P.A.; Ye, W.; Brown, M.B.; Williams, M.J. Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 1: Adrenocortical and pituitary glucocorticoid responsiveness. Alcohol. Clin. Exp. Res. 2005, 29, 517–527. [Google Scholar] [CrossRef] [PubMed]
  230. Adinoff, B.; Krebaum, S.R.; Chandler, P.A.; Ye, W.; Brown, M.B.; Williams, M.J. Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 2: Response to ovine corticotropin-releasing factor and naloxone. Alcohol. Clin. Exp. Res. 2005, 29, 528–537. [Google Scholar] [CrossRef] [PubMed]
  231. Baumeister, D.; Lightman, S.L.; Pariante, C.M. The Interface of Stress and the HPA Axis in Behavioural Phenotypes of Mental Illness. Curr. Top. Behav. Neurosci. 2014, 18, 13–24. [Google Scholar] [CrossRef] [PubMed]
  232. Schule, C.; Nothdurfter, C.; Rupprecht, R. The role of allopregnanolone in depression and anxiety. Prog. Neurobiol. 2014, 113, 79–87. [Google Scholar] [CrossRef] [PubMed]
  233. Rasmusson, A.M.; Marx, C.E.; Pineles, S.L.; Locci, A.; Scioli-Salter, E.R.; Nillni, Y.I.; Liang, J.J.; Pinna, G. Neuroactive steroids and PTSD treatment. Neurosci. Lett. 2017, 649, 156–163. [Google Scholar] [CrossRef]
  234. Decavel, C.; Van den Pol, A.N. GABA: A dominant neurotransmitter in the hypothalamus. J. Comp. Neurol. 1990, 302, 1019–1037. [Google Scholar] [CrossRef]
  235. Decavel, C.; van den Pol, A.N. Converging GABA- and glutamate-immunoreactive axons make synaptic contact with identified hypothalamic neurosecretory neurons. J. Comp. Neurol. 1992, 316, 104–116. [Google Scholar] [CrossRef]
  236. Rasmusson, A.M.; Pinna, G.; Paliwal, P.; Weisman, D.; Gottschalk, C.; Charney, D.; Krystal, J.; Guidotti, A. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol. Psychiatry 2006, 60, 704–713. [Google Scholar] [CrossRef] [PubMed]
  237. Serra, M.; Pisu, M.G.; Littera, M.; Papi, G.; Sanna, E.; Tuveri, F.; Usala, L.; Purdy, R.H.; Biggio, G. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. J. Neurochem. 2000, 75, 732–740. [Google Scholar] [CrossRef] [PubMed]
  238. Dong, E.; Matsumoto, K.; Uzunova, V.; Sugaya, I.; Takahata, H.; Nomura, H.; Watanabe, H.; Costa, E.; Guidotti, A. Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc. Natl. Acad. Sci. USA 2001, 98, 2849–2854. [Google Scholar] [CrossRef] [PubMed]
  239. Serra, M.; Pisu, M.G.; Floris, I.; Biggio, G. Social isolation-induced changes in the hypothalamic-pituitary-adrenal axis in the rat. Stress 2005, 8, 259–264. [Google Scholar] [CrossRef] [PubMed]
  240. Pisu, M.G.; Garau, A.; Boero, G.; Biggio, F.; Pibiri, V.; Dore, R.; Locci, V.; Paci, E.; Porcu, P.; Serra, M. Sex differences in the outcome of juvenile social isolation on HPA axis function in rats. Neuroscience 2016, 320, 172–182. [Google Scholar] [CrossRef] [PubMed]
  241. Boero, G.; Pisu, M.G.; Biggio, F.; Muredda, L.; Carta, G.; Banni, S.; Paci, E.; Follesa, P.; Concas, A.; Porcu, P.; et al. Impaired glucocorticoid-mediated HPA axis negative feedback induced by juvenile social isolation in male rats. Neuropharmacology 2018, 133, 242–253. [Google Scholar] [CrossRef] [PubMed]
  242. Blaine, S.K.; Nautiyal, N.; Hart, R.; Guarnaccia, J.B.; Sinha, R. Craving, cortisol and behavioral alcohol motivation responses to stress and alcohol cue contexts and discrete cues in binge and non-binge drinkers. Addict. Biol. 2019, 24, 1096–1108. [Google Scholar] [CrossRef] [PubMed]
  243. Pariante, C.M.; Lightman, S.L. The HPA axis in major depression: Classical theories and new developments. Trends Neurosci. 2008, 31, 464–468. [Google Scholar] [CrossRef] [PubMed]
  244. Romeo, E.; Ströhle, A.; Spalletta, G.; di Michele, F.; Hermann, B.; Holsboer, F.; Pasini, A.; Rupprecht, R. Effects of antidepressant treatment on neuroactive steroids in major depression. Am. J. Psychiatry 1998, 155, 910–913. [Google Scholar] [CrossRef]
  245. Uzunova, V.; Sheline, Y.; Davis, J.M.; Rasmusson, A.; Uzunov, D.P.; Costa, E.; Guidotti, A. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc. Natl. Acad. Sci. USA 1998, 95, 3239–3244. [Google Scholar] [CrossRef]
  246. Ströhle, A.; Romeo, E.; Hermann, B.; Pasini, A.; Spalletta, G.; di Michele, F.; Holsboer, F.; Rupprecht, R. Concentrations of 3a-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol. Psychiatry 1999, 45, 274–277. [Google Scholar] [CrossRef] [PubMed]
  247. Deligiannidis, K.M.; Sikoglu, E.M.; Shaffer, S.A.; Frederick, B.; Svenson, A.E.; Kopoyan, A.; Kosma, C.A.; Rothschild, A.J.; Moore, C.M. GABAergic neuroactive steroids and resting-state functional connectivity in postpartum depression: A preliminary study. J. Psychiatr. Res. 2013, 47, 816–828. [Google Scholar] [CrossRef] [PubMed]
  248. Deligiannidis, K.M.; Kroll-Desrosiers, A.R.; Mo, S.; Nguyen, H.P.; Svenson, A.; Jaitly, N.; Hall, J.E.; Barton, B.A.; Rothschild, A.J.; Shaffer, S.A. Peripartum neuroactive steroid and γ-aminobutyric acid profiles in women at-risk for postpartum depression. Psychoneuroendocrinology 2016, 70, 98–107. [Google Scholar] [CrossRef] [PubMed]
  249. Magiakou, M.A.; Mastorakos, G.; Rabin, D.; Dubbert, B.; Gold, P.W.; Chrousos, G.P. Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: Implications for the increase in psychiatric manifestations at this time. J. Clin. Endocrinol. Metab. 1996, 81, 1912–1917. [Google Scholar] [CrossRef] [PubMed]
  250. Meltzer-Brody, S. New insights into perinatal depression: Pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin. Neurosci. 2011, 13, 89–100. [Google Scholar] [CrossRef] [PubMed]
  251. Maguire, J.; Mody, I. GABA(A)R plasticity during pregnancy: Relevance to postpartum depression. Neuron 2008, 59, 207–213. [Google Scholar] [CrossRef] [PubMed]
  252. Sarkar, J.; Wakefield, S.; MacKenzie, G.; Moss, S.J.; Maguire, J. Neurosteroidogenesis is required for the physiological response to stress: Role of neurosteroid-sensitive GABAA receptors. J. Neurosci. 2011, 31, 18198–18210. [Google Scholar] [CrossRef]
  253. Maguire, J.; Mody, I. Behavioral Deficits in Juveniles Mediated by Maternal Stress Hormones in Mice. Neural Plast. 2016, 2016, 2762518. [Google Scholar] [CrossRef]
  254. Patchev, V.K.; Shoaib, M.; Holsboer, F.; Almeida, O.F.X. The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus. Neuroscience 1994, 62, 265–271. [Google Scholar] [CrossRef]
  255. Patchev, V.K.; Hassan, A.H.S.; Holsboer, F.; Almeida, O.F.X. The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus. Neuropsychopharmacology 1996, 15, 533–540. [Google Scholar] [CrossRef]
  256. Owens, M.J.; Ritchie, J.C.; Nemeroff, C.B. 5 alpha-pregnane-3 alpha, 21-diol-20-one (THDOC) attenuates mild stress-induced increases in plasma corticosterone via a non-glucocorticoid mechanism: Comparison with alprazolam. Brain Res. 1992, 573, 353–355. [Google Scholar] [CrossRef] [PubMed]
  257. Dantzer, R.; O’Connor, J.C.; Freund, G.G.; Johnson, R.W.; Kelley, K.W. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat. Rev. Neurosci. 2008, 9, 46–56. [Google Scholar] [CrossRef] [PubMed]
  258. Kendall-Tackett, K. A new paradigm for depression in new mothers: The central role of inflammation and how breastfeeding and anti-inflammatory treatments protect maternal mental health. Int. Breastfeed. J. 2007, 2, 6. [Google Scholar] [CrossRef] [PubMed]
  259. Yamamoto, M.; Sato, S.; Hemmi, H.; Uematsu, S.; Hoshino, K.; Kaisho, T.; Takeuchi, O.; Takeda, K.; Akira, S. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 2003, 4, 1144–1150. [Google Scholar] [CrossRef] [PubMed]
  260. Yamamoto, M.; Sato, S.; Hemmi, H.; Hoshino, K.; Kaisho, T.; Sanjo, H.; Takeuchi, O.; Sugiyama, M.; Okabe, M.; Takeda, K.; et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003, 301, 640–643. [Google Scholar] [CrossRef] [PubMed]
  261. Ullah, M.O.; Sweet, M.J.; Mansell, A.; Kellie, S.; Kobe, B. TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target. J. Leukoc. Biol. 2016, 100, 27–45. [Google Scholar] [CrossRef] [PubMed]
  262. Vijay, K. Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int. Immunopharmacol. 2018, 59, 391–412. [Google Scholar] [CrossRef] [PubMed]
  263. L’Episcopo, F.; Tirolo, C.; Serapide, M.F.; Caniglia, S.; Testa, N.; Leggio, L.; Vivarelli, S.; Iraci, N.; Pluchino, S.; Marchetti, B. Microglia Polarization, Gene-Environment Interactions and Wnt/β-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain. Front. Aging Neurosci. 2018, 10, 12. [Google Scholar] [CrossRef] [PubMed]
  264. Szepesi, Z.; Manouchehrian, O.; Bachiller, S.; Deierborg, T. Bidirectional Microglia-Neuron Communication in Health and Disease. Front. Cell. Neurosci. 2018, 12, 323. [Google Scholar] [CrossRef]
  265. Biber, K.; Neumann, H.; Inoue, K.; Boddeke, H.W. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci. 2007, 30, 596–602. [Google Scholar] [CrossRef]
  266. Pocock, J.M.; Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007, 30, 527–535. [Google Scholar] [CrossRef] [PubMed]
  267. Ransohoff, R.M.; Perry, V.H. Microglial physiology: Unique stimuli, specialized responses. Annu. Rev. Immunol. 2009, 27, 119–145. [Google Scholar] [CrossRef] [PubMed]
  268. Fields, R.D.; Woo, D.H.; Basser, P.J. Glial Regulation of the Neuronal Connectome through Local and Long-Distant Communication. Neuron 2015, 86, 374–386. [Google Scholar] [CrossRef] [PubMed]
  269. Perea, G.; Sur, M.; Araque, A. Neuron-glia networks: Integral gear of brain function. Front. Cell. Neurosci. 2014, 8, 378. [Google Scholar] [CrossRef] [PubMed]
  270. Peferoen, L.; Kipp, M.; van der Valk, P.; van Noort, J.M.; Amor, S. Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 2014, 141, 302–313. [Google Scholar] [CrossRef] [PubMed]
  271. Maroso, M.; Balosso, S.; Ravizza, T.; Iori, V.; Wright, C.I.; French, J.; Vezzani, A. Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 2011, 8, 304–315. [Google Scholar] [CrossRef]
  272. Paudel, Y.N.; Angelopoulou, E.; Akyuz, E.; Piperi, C.; Othman, I.; Shaikh, M.F. Role of Innate Immune Receptor TLR4 and its endogenous ligands in epileptogenesis. Pharmacol. Res. 2020, 160, 105172. [Google Scholar] [CrossRef]
  273. Maroso, M.; Balosso, S.; Ravizza, T.; Liu, J.; Aronica, E.; Iyer, A.M.; Rossetti, C.; Molteni, M.; Casalgrandi, M.; Manfredi, A.A.; et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med. 2010, 16, 413–419. [Google Scholar] [CrossRef] [PubMed]
  274. Gross, A.; Benninger, F.; Madar, R.; Illouz, T.; Griffioen, K.; Steiner, I.; Offen, D.; Okun, E. Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice. Epilepsia 2017, 58, 586–596. [Google Scholar] [CrossRef] [PubMed]
  275. Lovelock, D.F.; Randall, P.A.; Van Voorhies, K.; Vetreno, R.P.; Crews, F.T.; Besheer, J. Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats. Pharmacol. Biochem. Behav. 2022, 216, 173379. [Google Scholar] [CrossRef]
  276. Tanga, F.Y.; Nutile-McMenemy, N.; DeLeo, J.A. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc. Natl. Acad. Sci. USA 2005, 102, 5856–5861. [Google Scholar] [CrossRef] [PubMed]
  277. Cao, L.; Tanga, F.Y.; DeLeo, J.A. The contributing role of CD14 in toll-like receptor 4 dependent neuropathic pain. Neuroscience 2009, 158, 896–903. [Google Scholar] [CrossRef]
  278. Chen, W.; Lu, Z. Upregulated TLR3 Promotes Neuropathic Pain by Regulating Autophagy in Rat with L5 Spinal Nerve Ligation Model. Neurochem. Res. 2017, 42, 634–643. [Google Scholar] [CrossRef] [PubMed]
  279. He, L.; Han, G.; Wu, S.; Du, S.; Zhang, Y.; Liu, W.; Jiang, B.; Zhang, L.; Xia, S.; Jia, S.; et al. Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons. Brain Behav. Immun. 2020, 87, 840–851. [Google Scholar] [CrossRef]
  280. Zhang, Z.-J.; Guo, J.-S.; Li, S.-S.; Wu, X.-B.; Cao, D.-L.; Jiang, B.-C.; Jing, P.-B.; Bai, X.-Q.; Li, C.-H.; Wu, Z.-H.; et al. TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. J. Exp. Med. 2018, 215, 3019–3037. [Google Scholar] [CrossRef]
  281. Yang, H.; Wu, L.; Deng, H.; Chen, Y.; Zhou, H.; Liu, M.; Wang, S.; Zheng, L.; Zhu, L.; Lv, X. Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia. J. Neuroinflammation 2020, 17, 154. [Google Scholar] [CrossRef]
  282. Colleselli, K.; Stierschneider, A.; Wiesner, C. An Update on Toll-like Receptor 2, Its Function and Dimerization in Pro- and Anti-Inflammatory Processes. Int. J. Mol. Sci. 2023, 24, 12464. [Google Scholar] [CrossRef] [PubMed]
  283. Siegemund, S.; Sauer, K. Balancing pro- and anti-inflammatory TLR4 signaling. Nat. Immunol. 2012, 13, 1031–1033. [Google Scholar] [CrossRef]
  284. Aksoy, E.; Taboubi, S.; Torres, D.; Delbauve, S.; Hachani, A.; Whitehead, M.A.; Pearce, W.P.; Berenjeno, I.M.; Nock, G.; Filloux, A.; et al. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat. Immunol. 2012, 13, 1045–1054. [Google Scholar] [CrossRef]
  285. Ramakrishna, C.; Kujawski, M.; Chu, H.; Li, L.; Mazmanian, S.K.; Cantin, E.M. Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis. Nat. Commun. 2019, 10, 2153. [Google Scholar] [CrossRef]
  286. Dasgupta, S.; Erturk-Hasdemir, D.; Ochoa-Reparaz, J.; Reinecker, H.C.; Kasper, D.L. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 2014, 15, 413–423. [Google Scholar] [CrossRef]
  287. Round, J.L.; Mazmanian, S.K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl. Acad. Sci. USA 2010, 107, 12204–12209. [Google Scholar] [CrossRef] [PubMed]
  288. Nguyen, B.N.; Chávez-Arroyo, A.; Cheng, M.I.; Krasilnikov, M.; Louie, A.; Portnoy, D.A. TLR2 and endosomal TLR-mediated secretion of IL-10 and immune suppression in response to phagosome-confined Listeria monocytogenes. PLoS Pathog. 2020, 16, e1008622. [Google Scholar] [CrossRef]
  289. Hoppstädter, J.; Dembek, A.; Linnenberger, R.; Dahlem, C.; Barghash, A.; Fecher-Trost, C.; Fuhrmann, G.; Koch, M.; Kraegeloh, A.; Huwer, H.; et al. Toll-Like Receptor 2 Release by Macrophages: An Anti-inflammatory Program Induced by Glucocorticoids and Lipopolysaccharide. Front. Immunol. 2019, 10, 1634. [Google Scholar] [CrossRef]
  290. Zamora-Pineda, J.; Kalinina, O.; Sperling, A.I.; Knight, K.L. Mechanism of TLR4-Mediated Anti-Inflammatory Response Induced by Exopolysaccharide from the Probiotic Bacillus subtilis. J. Immunol. 2023, 211, 1232–1239. [Google Scholar] [CrossRef]
  291. Leibler, C.; John, S.; Elsner, R.A.; Thomas, K.B.; Smita, S.; Joachim, S.; Levack, R.C.; Callahan, D.J.; Gordon, R.A.; Bastacky, S.; et al. Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus. Nat. Immunol. 2022, 23, 1457–1469. [Google Scholar] [CrossRef] [PubMed]
  292. Zhang, S.; Cao, X. TLR9 triggers MyD88-independent anti-inflammatory signaling in lupus. Trends Immunol. 2023, 44, 153–155. [Google Scholar] [CrossRef]
  293. Verma, R.; Kim, J.Y. 1,25-Dihydroxyvitamin D3 Facilitates M2 Polarization and Upregulates TLR10 Expression on Human Microglial Cells. Neuroimmunomodulation 2016, 23, 75–80. [Google Scholar] [CrossRef]
  294. Lei, B.; Mace, B.; Dawson, H.N.; Warner, D.S.; Laskowitz, D.T.; James, M.L. Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia. PLoS ONE 2014, 9, e103969. [Google Scholar] [CrossRef]
  295. Lobo-Silva, D.; Carriche, G.M.; Castro, A.G.; Roque, S.; Saraiva, M. Balancing the immune response in the brain: IL-10 and its regulation. J. Neuroinflamm. 2016, 13, 297. [Google Scholar] [CrossRef] [PubMed]
  296. Ledeboer, A.; Brevé, J.J.; Wierinckx, A.; van der Jagt, S.; Bristow, A.F.; Leysen, J.E.; Tilders, F.J.; Van Dam, A.M. Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. Eur. J. Neurosci. 2002, 16, 1175–1185. [Google Scholar] [CrossRef]
  297. Balasingam, V.; Yong, V.W. Attenuation of astroglial reactivity by interleukin-10. J. Neurosci. 1996, 16, 2945–2955. [Google Scholar] [CrossRef]
  298. Norden, D.M.; Fenn, A.M.; Dugan, A.; Godbout, J.P. TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation. Glia 2014, 62, 881–895. [Google Scholar] [CrossRef]
  299. Makar, T.K.; Bever, C.T.; Singh, I.S.; Royal, W.; Sahu, S.N.; Sura, T.P.; Sultana, S.; Sura, K.T.; Patel, N.; Dhib-Jalbut, S.; et al. Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J. Neuroimmunol. 2009, 210, 40–51. [Google Scholar] [CrossRef]
  300. Jiang, Y.; Wei, N.; Zhu, J.; Lu, T.; Chen, Z.; Xu, G.; Liu, X. Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat. Mediat. Inflamm. 2010, 2010, 372423. [Google Scholar] [CrossRef]
  301. Xu, D.; Lian, D.; Wu, J.; Liu, Y.; Zhu, M.; Sun, J.; He, D.; Li, L. Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis. J. Neuroinflamm. 2017, 14, 156. [Google Scholar] [CrossRef]
  302. Morrow, A.L.; Boero, G.; Balan, I. Emerging Evidence for Endogenous Neurosteroid Modulation of Pro-Inflammatory and Anti-Inflammatory Pathways that Impact Neuropsychiatric Disease. Neurosci. Biobehav. Rev. 2024, 158, 105558. [Google Scholar] [CrossRef] [PubMed]
  303. Roy, S.; Sipthorp, J.; Mahata, B.; Pramanik, J.; Hennrich, M.L.; Gavin, A.C.; Ley, S.V.; Teichmann, S.A. CLICK-enabled analogues reveal pregnenolone interactomes in cancer and immune cells. iScience 2021, 24, 102485. [Google Scholar] [CrossRef]
  304. Roy, S.; Roy, S.; Mahata, B.; Pramanik, J.; Hennrich, M.L.; Gavin, A.C.; Teichmann, S.A. CLICK-chemoproteomics and molecular dynamics simulation reveals pregnenolone targets and their binding conformations in Th2 cells. Front. Immunol. 2023, 14, 1229703. [Google Scholar] [CrossRef] [PubMed]
  305. McCoy, K.L. Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation. Mediat. Inflamm. 2016, 2016, 5831315. [Google Scholar] [CrossRef]
  306. Duncan, M.; Galic, M.A.; Wang, A.; Chambers, A.P.; McCafferty, D.M.; McKay, D.M.; Sharkey, K.A.; Pittman, Q.J. Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013, 305, R224–R231. [Google Scholar] [CrossRef]
  307. Fedotcheva, T.A.; Fedotcheva, N.I.; Shimanovsky, N.L. Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation. Biomolecules 2022, 12, 1299. [Google Scholar] [CrossRef] [PubMed]
  308. Jitprasertwong, P.; Charadram, N.; Kumphune, S.; Pongcharoen, S.; Sirisinha, S. Female sex hormones modulate Porphyromonas gingivalis lipopolysaccharide-induced Toll-like receptor signaling in primary human monocytes. J. Periodontal Res. 2016, 51, 395–406. [Google Scholar] [CrossRef] [PubMed]
  309. Giannoni, E.; Guignard, L.; Reymond, M.K.; Perreau, M.; Roth-Kleiner, M.; Calandra, T.; Roger, T. Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns. Infect. Immun. 2011, 79, 2690–2698. [Google Scholar] [CrossRef] [PubMed]
  310. Müller, E.; Kerschbaum, H.H. Progesterone and its metabolites 5-dihydroprogesterone and 5-3-tetrahydroprogesterone decrease LPS-induced NO release in the murine microglial cell line, BV-2. Neuro Endocrinol. Lett. 2006, 27, 675–678. [Google Scholar] [PubMed]
  311. Salama, R.M.; Tadros, M.G.; Schaalan, M.F.; Bahaa, N.; Abdel-Tawab, A.M.; Khalifa, A.E. Potential neuroprotective effect of androst-5-ene-3β, 17β-diol (ADIOL) on the striatum, and substantia nigra in Parkinson’s disease rat model. J. Cell. Physiol. 2018, 233, 5981–6000. [Google Scholar] [CrossRef]
  312. Auci, D.; Nicoletti, F.; Mangano, K.; Pieters, R.; Nierkens, S.; Morgan, L.; Offner, H.; Frincke, J.; Reading, C. Anti-inflammatory and Immune Regulatory Properties of 5-Androsten-3β, 17β-Diol (HE2100), and Synthetic Analogue HE3204: Implications for Treatment of Autoimmune Diseases. Ann. N. Y. Acad. Sci. 2005, 1051, 730–742. [Google Scholar] [CrossRef] [PubMed]
  313. Kalakh, S.; Mouihate, A. Androstenediol Reduces Demyelination-Induced Axonopathy in the Rat Corpus Callosum: Impact on Microglial Polarization. Front. Cell. Neurosci. 2017, 11, 49. [Google Scholar] [CrossRef] [PubMed]
  314. Zelcer, N.; Khanlou, N.; Clare, R.; Jiang, Q.; Reed-Geaghan, E.G.; Landreth, G.E.; Vinters, H.V.; Tontonoz, P. Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors. Proc. Natl. Acad. Sci. USA 2007, 104, 10601–10606. [Google Scholar] [CrossRef] [PubMed]
  315. Hanna, D.M.; Tadros, M.G.; Khalifa, A.E. ADIOL protects against 3-NP-induced neurotoxicity in rats: Possible impact of its anti-oxidant, anti-inflammatory and anti-apoptotic actions. Prog. Neuropsychopharmacol. Biol. Psychiatry 2015, 60, 36–51. [Google Scholar] [CrossRef]
  316. Nicoletti, F.; Auci, D.L.; Mangano, K.; Flores-Riveros, J.; Villegas, S.; Frincke, J.M.; Reading, C.L.; Offner, H. 5-Androstenediol Ameliorates Pleurisy, Septic Shock, and Experimental Autoimmune Encephalomyelitis in Mice. Autoimmune Dis. 2010, 2010, 757432. [Google Scholar] [CrossRef] [PubMed]
  317. Vegeto, E.; Benedusi, V.; Maggi, A. Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases. Front. Neuroendocrinol. 2008, 29, 507–519. [Google Scholar] [CrossRef] [PubMed]
  318. Han, Q.; Yang, D.; Yin, C.; Zhang, J. Androgen Receptor (AR)-TLR4 Crosstalk Mediates Gender Disparities in Hepatocellular Carcinoma Incidence and Progression. J. Cancer 2020, 11, 1094–1103. [Google Scholar] [CrossRef] [PubMed]
  319. Ainola, M.; Porola, P.; Takakubo, Y.; Przybyla, B.; Kouri, V.P.; Tolvanen, T.A.; Hänninen, A.; Nordström, D.C. Activation of plasmacytoid dendritic cells by apoptotic particles—Mechanism for the loss of immunological tolerance in Sjögren’s syndrome. Clin. Exp. Immunol. 2017, 191, 301–310. [Google Scholar] [CrossRef] [PubMed]
  320. Wang, M.J.; Huang, H.M.; Chen, H.L.; Kuo, J.S.; Jeng, K.C. Dehydroepiandrosterone inhibits lipopolysaccharide-induced nitric oxide production in BV-2 microglia. J. Neurochem. 2001, 77, 830–838. [Google Scholar] [CrossRef] [PubMed]
  321. Schurr, M.J.; Fabian, T.C.; Croce, M.A.; Varnavas, L.E.; Proctor, K.G. Dehydroepiandrosterone, an endogenous immune modulator, after traumatic shock. Shock 1997, 7, 55–59. [Google Scholar] [CrossRef] [PubMed]
  322. Zorrilla, E.P.; Luborsky, L.; McKay, J.R.; Rosenthal, R.; Houldin, A.; Tax, A.; McCorkle, R.; Seligman, D.A.; Schmidt, K. The relationship of depression and stressors to immunological assays: A meta-analytic review. Brain Behav. Immun. 2001, 15, 199–226. [Google Scholar] [CrossRef] [PubMed]
  323. Howren, M.B.; Lamkin, D.M.; Suls, J. Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosom. Med. 2009, 71, 171–186. [Google Scholar] [CrossRef] [PubMed]
  324. Dowlati, Y.; Herrmann, N.; Swardfager, W.; Liu, H.; Sham, L.; Reim, E.K.; Lanctot, K.L. A meta-analysis of cytokines in major depression. Biol. Psychiatry 2010, 67, 446–457. [Google Scholar] [CrossRef]
  325. Dantzer, R.; O’Connor, J.C.; Lawson, M.A.; Kelley, K.W. Inflammation-associated depression: From serotonin to kynurenine. Psychoneuroendocrinology 2011, 36, 426–436. [Google Scholar] [CrossRef]
  326. Bhattacharya, A.; Derecki, N.C.; Lovenberg, T.W.; Drevets, W.C. Role of neuro-immunological factors in the pathophysiology of mood disorders. Psychopharmacology 2016, 233, 1623–1636. [Google Scholar] [CrossRef]
  327. Vichaya, E.G.; Laumet, G.; Christian, D.L.; Grossberg, A.J.; Estrada, D.J.; Heijnen, C.J.; Kavelaars, A.; Dantzer, R. Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase. Neuropsychopharmacology 2019, 44, 364–371. [Google Scholar] [CrossRef]
  328. Bullmore, E. The art of medicine: Inflamed depression. Lancet 2018, 392, 1189–1190. [Google Scholar] [CrossRef]
  329. Achtyes, E.; Keaton, S.A.; Smart, L.; Burmeister, A.R.; Heilman, P.L.; Krzyzanowski, S.; Nagalla, M.; Guillemin, G.J.; Escobar Galvis, M.L.; Lim, C.K.; et al. Inflammation and kynurenine pathway dysregulation in post-partum women with severe and suicidal depression. Brain Behav. Immun. 2020, 83, 239–247. [Google Scholar] [CrossRef]
  330. Sha, Q.; Madaj, Z.; Keaton, S.; Escobar Galvis, M.L.; Smart, L.; Krzyzanowski, S.; Fazleabas, A.T.; Leach, R.; Postolache, T.T.; Achtyes, E.D.; et al. Cytokines and tryptophan metabolites can predict depressive symptoms in pregnancy. Transl. Psychiatry 2022, 12, 35. [Google Scholar] [CrossRef]
  331. Kim, T.D.; Lee, S.; Yoon, S. Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective. Antioxidants 2020, 9, 107. [Google Scholar] [CrossRef]
  332. Michopoulos, V.; Powers, A.; Gillespie, C.F.; Ressler, K.J.; Jovanovic, T. Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond. Neuropsychopharmacology 2017, 42, 254–270. [Google Scholar] [CrossRef]
  333. Miller, M.W.; Lin, A.P.; Wolf, E.J.; Miller, D.R. Oxidative Stress, Inflammation, and Neuroprogression in Chronic PTSD. Harv. Rev. Psychiatry 2018, 26, 57–69. [Google Scholar] [CrossRef] [PubMed]
  334. Hajebrahimi, B.; Bagheri, M.; Hassanshahi, G.; Nazari, M.; Bidaki, R.; Khodadadi, H.; Arababadi, M.K.; Kennedy, D. The adapter proteins of TLRs, TRIF and MYD88, are upregulated in depressed individuals. Int. J. Psychiatry Clin. Pract. 2014, 18, 41–44. [Google Scholar] [CrossRef]
  335. Wu, M.K.; Huang, T.L.; Huang, K.W.; Huang, Y.L.; Hung, Y.Y. Association between toll-like receptor 4 expression and symptoms of major depressive disorder. Neuropsychiatr. Dis. Treat. 2015, 11, 1853–1857. [Google Scholar] [CrossRef] [PubMed]
  336. Hung, Y.Y.; Kang, H.Y.; Huang, K.W.; Huang, T.L. Association between toll-like receptors expression and major depressive disorder. Psychiatry Res. 2014, 220, 283–286. [Google Scholar] [CrossRef]
  337. Pandey, G.N.; Rizavi, H.S.; Ren, X.; Fareed, J.; Hoppensteadt, D.A.; Roberts, R.C.; Conley, R.R.; Dwivedi, Y. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J. Psychiatr. Res. 2012, 46, 57–63. [Google Scholar] [CrossRef]
  338. Pandey, G.N.; Rizavi, H.S.; Bhaumik, R.; Ren, X. Innate immunity in the postmortem brain of depressed and suicide subjects: Role of Toll-like receptors. Brain Behav. Immun. 2019, 75, 101–111. [Google Scholar] [CrossRef] [PubMed]
  339. Corwin, E.J.; Johnston, N.; Pugh, L. Symptoms of postpartum depression associated with elevated levels of interleukin-1 beta during the first month postpartum. Biol. Res. Nurs. 2008, 10, 128–133. [Google Scholar] [CrossRef]
  340. Cassidy-Bushrow, A.E.; Peters, R.M.; Johnson, D.A.; Templin, T.N. Association of depressive symptoms with inflammatory biomarkers among pregnant African-American women. J. Reprod. Immunol. 2012, 94, 202–209. [Google Scholar] [CrossRef] [PubMed]
  341. Yurashevich, M.; Cooter Wright, M.; Sims, S.C.; Tan, H.S.; Berger, M.; Ji, R.R.; Habib, A.S. Inflammatory changes in the plasma and cerebrospinal fluid of patients with persistent pain and postpartum depression after elective Cesarean delivery: An exploratory prospective cohort study. Can. J. Anaesth. 2023, 70, 1917–1927. [Google Scholar] [CrossRef]
  342. Boufidou, F.; Lambrinoudaki, I.; Argeitis, J.; Zervas, I.M.; Pliatsika, P.; Leonardou, A.A.; Petropoulos, G.; Hasiakos, D.; Papadias, K.; Nikolaou, C. CSF and plasma cytokines at delivery and postpartum mood disturbances. J. Affect. Disord. 2009, 115, 287–292. [Google Scholar] [CrossRef] [PubMed]
  343. Maes, M.; Lin, A.H.; Ombelet, W.; Stevens, K.; Kenis, G.; De Jongh, R.; Cox, J.; Bosmans, E. Immune activation in the early puerperium is related to postpartum anxiety and depressive symptoms. Psychoneuroendocrinology 2000, 25, 121–137. [Google Scholar] [CrossRef]
  344. Fransson, E.; Dubicke, A.; Byström, B.; Ekman-Ordeberg, G.; Hjelmstedt, A.; Lekander, M. Negative emotions and cytokines in maternal and cord serum at preterm birth. Am. J. Reprod. Immunol. 2012, 67, 506–514. [Google Scholar] [CrossRef]
  345. Picard, K.; Bisht, K.; Poggini, S.; Garofalo, S.; Golia, M.T.; Basilico, B.; Abdallah, F.; Ciano Albanese, N.; Amrein, I.; Vernoux, N.; et al. Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain Behav. Immun. 2021, 97, 423–439. [Google Scholar] [CrossRef]
  346. Sierra, A.; Gottfried-Blackmore, A.; Milner, T.A.; McEwen, B.S.; Bulloch, K. Steroid hormone receptor expression and function in microglia. Glia 2008, 56, 659–674. [Google Scholar] [CrossRef]
  347. Hermoso, M.A.; Matsuguchi, T.; Smoak, K.; Cidlowski, J.A. Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression. Mol. Cell. Biol. 2004, 24, 4743–4756. [Google Scholar] [CrossRef]
  348. Busillo, J.M.; Azzam, K.M.; Cidlowski, J.A. Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome. J. Biol. Chem. 2011, 286, 38703–38713. [Google Scholar] [CrossRef]
  349. Jones, K.A.; Thomsen, C. The role of the innate immune system in psychiatric disorders. Mol. Cell. Neurosci. 2013, 53, 52–62. [Google Scholar] [CrossRef] [PubMed]
  350. Liddelow, S.A.; Marsh, S.E.; Stevens, B. Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime? Trends Immunol. 2020, 41, 820–835. [Google Scholar] [CrossRef]
  351. Jha, M.K.; Jo, M.; Kim, J.H.; Suk, K. Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation. Neuroscientist 2019, 25, 227–240. [Google Scholar] [CrossRef]
  352. Charles-Messance, H.; Blot, G.; Couturier, A.; Vignaud, L.; Touhami, S.; Beguier, F.; Siqueiros, L.; Forster, V.; Barmo, N.; Augustin, S.; et al. IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis. J. Neuroinflammation 2020, 17, 1. [Google Scholar] [CrossRef]
  353. Gao, J.; Wang, H.; Liu, Y.; Li, Y.Y.; Chen, C.; Liu, L.M.; Wu, Y.M.; Li, S.; Yang, C. Glutamate and GABA imbalance promotes neuronal apoptosis in hippocampus after stress. Med. Sci. Monit. 2014, 20, 499–512. [Google Scholar] [CrossRef]
  354. Meyerhoff, D.J.; Mon, A.; Metzler, T.; Neylan, T.C. Cortical gamma-aminobutyric acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. Sleep 2014, 37, 893–900. [Google Scholar] [CrossRef]
  355. Nie, H.; Peng, Z.; Lao, N.; Wang, H.; Chen, Y.; Fang, Z.; Hou, W.; Gao, F.; Li, X.; Xiong, L.; et al. Rosmarinic acid ameliorates PTSD-like symptoms in a rat model and promotes cell proliferation in the hippocampus. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 51, 16–22. [Google Scholar] [CrossRef]
  356. Porcu, P.; Lallai, V.; Locci, A.; Catzeddu, S.; Serra, V.; Pisu, M.G.; Serra, M.; Dazzi, L.; Concas, A. Changes in stress-stimulated allopregnanolone levels induced by neonatal estradiol treatment are associated with enhanced dopamine release in adult female rats: Reversal by progesterone administration. Psychopharmacology 2017, 234, 749–760. [Google Scholar] [CrossRef]
  357. Kanes, S.J.; Colquhoun, H.; Doherty, J.; Raines, S.; Hoffmann, E.; Rubinow, D.R.; Meltzer-Brody, S. Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Hum. Psychopharmacol. 2017, 32, e2576. [Google Scholar] [CrossRef]
  358. Meltzer-Brody, S.; Howard, L.M.; Bergink, V.; Vigod, S.; Jones, I.; Munk-Olsen, T.; Honikman, S.; Milgrom, J. Postpartum psychiatric disorders. Nat. Rev. Dis. Primers 2018, 4, 18022. [Google Scholar] [CrossRef]
  359. Deligiannidis, K.M.; Meltzer-Brody, S.; Gunduz-Bruce, H.; Doherty, J.; Jonas, J.; Li, S.; Sankoh, A.J.; Silber, C.; Campbell, A.D.; Werneburg, B.; et al. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry 2021, 78, 951–959. [Google Scholar] [CrossRef]
  360. Gunduz-Bruce, H.; Silber, C.; Kaul, I.; Rothschild, A.J.; Riesenberg, R.; Sankoh, A.J.; Li, H.; Lasser, R.; Zorumski, C.F.; Rubinow, D.R.; et al. Trial of SAGE-217 in Patients with Major Depressive Disorder. N. Engl. J. Med. 2019, 381, 903–911. [Google Scholar] [CrossRef]
  361. Rasmusson, A.M.; Marx, C.E.; Jain, S.; Farfel, G.M.; Tsai, J.; Sun, X.; Geracioti, T.D.; Hamner, M.B.; Lohr, J.; Rosse, R.; et al. A randomized controlled trial of ganaxolone in posttraumatic stress disorder. Psychopharmacology 2017, 234, 2245–2257. [Google Scholar] [CrossRef]
  362. Walther, A.; Breidenstein, J.; Miller, R. Association of Testosterone Treatment with Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis. JAMA Psychiatry 2019, 76, 31–40. [Google Scholar] [CrossRef]
  363. Espallergues, J.; Mamiya, T.; Vallée, M.; Koseki, T.; Nabeshima, T.; Temsamani, J.; Laruelle, C.; Maurice, T. The antidepressant-like effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane in mice is related to changes in neuroactive steroid and monoamine levels. Neuropharmacology 2012, 62, 492–502. [Google Scholar] [CrossRef]
  364. Koonce, C.J.; Walf, A.A.; Frye, C.A. Trilostane exerts antidepressive effects among wild-type, but not estrogen receptor [beta] knockout mice. Neuroreport 2009, 20, 1047–1050. [Google Scholar] [CrossRef]
  365. He, J.; Crews, F.T. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp. Neurol. 2008, 210, 349–358. [Google Scholar] [CrossRef]
  366. Qin, L.; He, J.; Hanes, R.N.; Pluzarev, O.; Hong, J.S.; Crews, F.T. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J. Neuroinflamm. 2008, 5, 10. [Google Scholar] [CrossRef] [PubMed]
  367. Bull, C.; Syed, W.A.; Minter, S.C.; Bowers, M.S. Differential response of glial fibrillary acidic protein-positive astrocytes in the rat prefrontal cortex following ethanol self-administration. Alcohol. Clin. Exp. Res. 2015, 39, 650–658. [Google Scholar] [CrossRef] [PubMed]
  368. Cao, L.; Fu, M.; Kumar, S.; Kumar, A. Methamphetamine potentiates HIV-1 gp120-mediated autophagy via Beclin-1 and Atg5/7 as a pro-survival response in astrocytes. Cell Death Dis. 2016, 7, e2425. [Google Scholar] [CrossRef] [PubMed]
  369. Beardsley, P.M.; Hauser, K.F. Glial modulators as potential treatments of psychostimulant abuse. Adv. Pharmacol. 2014, 69, 1–69. [Google Scholar] [CrossRef]
  370. Kane, C.J.; Phelan, K.D.; Douglas, J.C.; Wagoner, G.; Johnson, J.W.; Xu, J.; Phelan, P.S.; Drew, P.D. Effects of ethanol on immune response in the brain: Region-specific changes in adolescent versus adult mice. Alcohol. Clin. Exp. Res. 2014, 38, 384–391. [Google Scholar] [CrossRef]
  371. Pascual, M.; Balino, P.; Aragon, C.M.; Guerri, C. Cytokines and chemokines as biomarkers of ethanol-induced neuroinflammation and anxiety-related behavior: Role of TLR4 and TLR2. Neuropharmacology 2015, 89, 352–359. [Google Scholar] [CrossRef] [PubMed]
  372. Pascual, M.; Calvo-Rodriguez, M.; Nunez, L.; Villalobos, C.; Urena, J.; Guerri, C. Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage. IUBMB Life 2021, 73, 900–915. [Google Scholar] [CrossRef] [PubMed]
  373. Wilhelm, C.J.; Fuller, B.E.; Huckans, M.; Loftis, J.M. Peripheral immune factors are elevated in women with current or recent alcohol dependence and associated with altered mood and memory. Drug Alcohol Depend. 2017, 176, 71–78. [Google Scholar] [CrossRef]
  374. Warden, A.S.; Azzam, M.; DaCosta, A.; Mason, S.; Blednov, Y.A.; Messing, R.O.; Mayfield, R.D.; Harris, R.A. Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice. Brain Behav. Immun. 2019, 77, 55–65. [Google Scholar] [CrossRef] [PubMed]
  375. Randall, P.A.; Vetreno, R.P.; Makhijani, V.H.; Crews, F.T.; Besheer, J. The Toll-Like Receptor 3 Agonist Poly(I:C) Induces Rapid and Lasting Changes in Gene Expression Related to Glutamatergic Function and Increases Ethanol Self-Administration in Rats. Alcohol. Clin. Exp. Res. 2019, 43, 48–60. [Google Scholar] [CrossRef]
  376. Blednov, Y.A.; Benavidez, J.M.; Geil, C.; Perra, S.; Morikawa, H.; Harris, R.A. Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav. Immun. 2011, 25 (Suppl. S1), S92–S105. [Google Scholar] [CrossRef] [PubMed]
  377. Fernandez-Lizarbe, S.; Montesinos, J.; Guerri, C. Ethanol induces TLR4/TLR2 association, triggering an inflammatory response in microglial cells. J. Neurochem. 2013, 126, 261–273. [Google Scholar] [CrossRef] [PubMed]
  378. Coleman, L.G., Jr.; Zou, J.; Qin, L.; Crews, F.T. HMGB1/IL-1beta complexes regulate neuroimmune responses in alcoholism. Brain Behav. Immun. 2018, 72, 61–77. [Google Scholar] [CrossRef] [PubMed]
  379. Ersche, K.D.; Hagan, C.C.; Smith, D.G.; Abbott, S.; Jones, P.S.; Apergis-Schoute, A.M.; Döffinger, R. Aberrant disgust responses and immune reactivity in cocaine-dependent men. Biol. Psychiatry 2014, 75, 140–147. [Google Scholar] [CrossRef] [PubMed]
  380. Levandowski, M.L.; Hess, A.R.; Grassi-Oliveira, R.; de Almeida, R.M. Plasma interleukin-6 and executive function in crack cocaine-dependent women. Neurosci. Lett. 2016, 628, 85–90. [Google Scholar] [CrossRef] [PubMed]
  381. Moreira, F.P.; Medeiros, J.R.; Lhullier, A.C.; Souza, L.D.; Jansen, K.; Portela, L.V.; Lara, D.R.; da Silva, R.A.; Wiener, C.D.; Oses, J.P. Cocaine abuse and effects in the serum levels of cytokines IL-6 and IL-10. Drug Alcohol Depend. 2016, 158, 181–185. [Google Scholar] [CrossRef]
  382. Shin, E.J.; Tran, H.Q.; Nguyen, P.T.; Jeong, J.H.; Nah, S.Y.; Jang, C.G.; Nabeshima, T.; Kim, H.C. Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis—A Review. Neurochem. Res. 2018, 43, 66–78. [Google Scholar] [CrossRef] [PubMed]
  383. Loftis, J.M.; Janowsky, A. Neuroimmune basis of methamphetamine toxicity. Int. Rev. Neurobiol. 2014, 118, 165–197. [Google Scholar] [CrossRef] [PubMed]
  384. Clark, K.H.; Wiley, C.A.; Bradberry, C.W. Psychostimulant abuse and neuroinflammation: Emerging evidence of their interconnection. Neurotox. Res. 2013, 23, 174–188. [Google Scholar] [CrossRef]
  385. Loftis, J.M.; Choi, D.; Hoffman, W.; Huckans, M.S. Methamphetamine causes persistent immune dysregulation: A cross-species, translational report. Neurotox. Res. 2011, 20, 59–68. [Google Scholar] [CrossRef]
  386. Gonçalves, J.; Martins, T.; Ferreira, R.; Milhazes, N.; Borges, F.; Ribeiro, C.F.; Malva, J.O.; Macedo, T.R.; Silva, A.P. Methamphetamine-induced early increase of IL-6 and TNF-alpha mRNA expression in the mouse brain. Ann. N. Y. Acad. Sci. 2008, 1139, 103–111. [Google Scholar] [CrossRef] [PubMed]
  387. LaVoie, M.J.; Card, J.P.; Hastings, T.G. Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity. Exp. Neurol. 2004, 187, 47–57. [Google Scholar] [CrossRef] [PubMed]
  388. Jean-Gilles, L.; Gran, B.; Constantinescu, C.S. Interaction between cytokines, cannabinoids and the nervous system. Immunobiology 2010, 215, 606–610. [Google Scholar] [CrossRef] [PubMed]
  389. Schwaeble, W.; Constantinescu, C.S. Relationship between cannabinoids and the immune system. Special Issue 8, 2010 Introduction. Immunobiology 2010, 215, 587. [Google Scholar] [CrossRef] [PubMed]
  390. Bayazit, H.; Selek, S.; Karababa, I.F.; Cicek, E.; Aksoy, N. Evaluation of Oxidant/Antioxidant Status and Cytokine Levels in Patients with Cannabis Use Disorder. Clin. Psychopharmacol. Neurosci. 2017, 15, 237–242. [Google Scholar] [CrossRef] [PubMed]
  391. Savage, S.M.; Donaldson, L.A.; Cherian, S.; Chilukuri, R.; White, V.A.; Sopori, M.L. Effects of cigarette smoke on the immune response. II. Chronic exposure to cigarette smoke inhibits surface immunoglobulin-mediated responses in B cells. Toxicol. Appl. Pharmacol. 1991, 111, 523–529. [Google Scholar] [CrossRef] [PubMed]
  392. Sopori, M.L.; Kozak, W. Immunomodulatory effects of cigarette smoke. J. Neuroimmunol. 1998, 83, 148–156. [Google Scholar] [CrossRef] [PubMed]
  393. Geng, Y.; Savage, S.M.; Johnson, L.J.; Seagrave, J.; Sopori, M.L. Effects of nicotine on the immune response. I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes. Toxicol. Appl. Pharmacol. 1995, 135, 268–278. [Google Scholar] [CrossRef] [PubMed]
  394. Guan, Y.Z.; Jin, X.D.; Guan, L.X.; Yan, H.C.; Wang, P.; Gong, Z.; Li, S.J.; Cao, X.; Xing, Y.L.; Gao, T.M. Nicotine inhibits microglial proliferation and is neuroprotective in global ischemia rats. Mol. Neurobiol. 2015, 51, 1480–1488. [Google Scholar] [CrossRef]
  395. O’Dell, L.E.; Purdy, R.H.; Covey, D.F.; Richardson, H.N.; Roberto, M.; Koob, G.F. Epipregnanolone and a novel synthetic neuroactive steroid reduce alcohol self-administration in rats. Pharmacol. Biochem. Behav. 2005, 81, 543–550. [Google Scholar] [CrossRef]
  396. Szabo-Pardi, T.A.; Barron, L.R.; Lenert, M.E.; Burton, M.D. Sensory Neuron TLR4 mediates the development of nerve-injury induced mechanical hypersensitivity in female mice. Brain Behav. Immun. 2021, 97, 42–60. [Google Scholar] [CrossRef]
  397. Agalave, N.M.; Larsson, M.; Abdelmoaty, S.; Su, J.; Baharpoor, A.; Lundbäck, P.; Palmblad, K.; Andersson, U.; Harris, H.; Svensson, C.I. Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain 2014, 155, 1802–1813. [Google Scholar] [CrossRef]
  398. Christianson, C.A.; Dumlao, D.S.; Stokes, J.A.; Dennis, E.A.; Svensson, C.I.; Corr, M.; Yaksh, T.L. Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain 2011, 152, 2881–2891. [Google Scholar] [CrossRef]
  399. Sorge, R.E.; Mapplebeck, J.C.; Rosen, S.; Beggs, S.; Taves, S.; Alexander, J.K.; Martin, L.J.; Austin, J.S.; Sotocinal, S.G.; Chen, D.; et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 2015, 18, 1081–1083. [Google Scholar] [CrossRef]
  400. Bartley, E.J.; Fillingim, R.B. Sex differences in pain: A brief review of clinical and experimental findings. Br. J. Anaesth. 2013, 111, 52–58. [Google Scholar] [CrossRef]
  401. Stokes, J.A.; Cheung, J.; Eddinger, K.; Corr, M.; Yaksh, T.L. Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. J. Neuroinflamm. 2013, 10, 148. [Google Scholar] [CrossRef]
  402. Sorge, R.E.; LaCroix-Fralish, M.L.; Tuttle, A.H.; Sotocinal, S.G.; Austin, J.S.; Ritchie, J.; Chanda, M.L.; Graham, A.C.; Topham, L.; Beggs, S.; et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J. Neurosci. 2011, 31, 15450–15454. [Google Scholar] [CrossRef]
  403. Stokes, J.A.; Corr, M.; Yaksh, T.L. Spinal toll-like receptor signaling and nociceptive processing: Regulatory balance between TIRAP and TRIF cascades mediated by TNF and IFNβ. Pain 2013, 154, 733–742. [Google Scholar] [CrossRef]
  404. Coronel, M.F.; Labombarda, F.; Villar, M.J.; De Nicola, A.F.; González, S.L. Progesterone Prevents Allodynia After Experimental Spinal Cord Injury. J. Pain 2011, 12, 71–83. [Google Scholar] [CrossRef]
  405. Coronel, M.F.; Labombarda, F.; Roig, P.; Villar, M.J.; De Nicola, A.F.; González, S.L. Progesterone prevents nerve injury-induced allodynia and spinal NMDA receptor upregulation in rats. Pain Med. 2011, 12, 1249–1261. [Google Scholar] [CrossRef]
  406. Cutler, S.M.; Cekic, M.; Miller, D.M.; Wali, B.; VanLandingham, J.W.; Stein, D.G. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J. Neurotrauma 2007, 24, 1475–1486. [Google Scholar] [CrossRef]
  407. Djebaili, M.; Guo, Q.; Pettus, E.H.; Hoffman, S.W.; Stein, D.G. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J. Neurotrauma 2005, 22, 106–118. [Google Scholar] [CrossRef]
  408. Pettus, E.H.; Wright, D.W.; Stein, D.G.; Hoffman, S.W. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005, 1049, 112–119. [Google Scholar] [CrossRef]
  409. O’Connor, C.A.; Cernak, I.; Vink, R. Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res. 2005, 1062, 171–174. [Google Scholar] [CrossRef]
  410. Sarkaki, A.R.; Khaksari Haddad, M.; Soltani, Z.; Shahrokhi, N.; Mahmoodi, M. Time- and dose-dependent neuroprotective effects of sex steroid hormones on inflammatory cytokines after a traumatic brain injury. J. Neurotrauma 2013, 30, 47–54. [Google Scholar] [CrossRef]
  411. Bianchi, V.E. The Anti-Inflammatory Effects of Testosterone. J. Endocr. Soc. 2019, 3, 91–107. [Google Scholar] [CrossRef]
  412. Mohamad, N.V.; Wong, S.K.; Wan Hasan, W.N.; Jolly, J.J.; Nur-Farhana, M.F.; Ima-Nirwana, S.; Chin, K.Y. The relationship between circulating testosterone and inflammatory cytokines in men. Aging Male 2019, 22, 129–140. [Google Scholar] [CrossRef]
  413. Lesnak, J.B.; Inoue, S.; Lima, L.; Rasmussen, L.; Sluka, K.A. Testosterone protects against the development of widespread muscle pain in mice. Pain 2020, 161, 2898–2908. [Google Scholar] [CrossRef]
  414. Naylor, J.C.; Kilts, J.D.; Strauss, J.L.; Szabo, S.T.; Dunn, C.E.; Wagner, H.R.; Hamer, R.M.; Shampine, L.J.; Zanga, J.R.; Marx, C.E. An exploratory pilot investigation of neurosteroids and self-reported pain in female Iraq/Afghanistan-era Veterans. J. Rehabil. Res. Dev. 2016, 53, 499–510. [Google Scholar] [CrossRef]
  415. Naylor, J.C.; Kilts, J.D.; Szabo, S.T.; Dunn, C.E.; Keefe, F.J.; Tupler, L.A.; Shampine, L.J.; Morey, R.A.; Strauss, J.L.; Hamer, R.M.; et al. Allopregnanolone Levels Are Inversely Associated with Self-Reported Pain Symptoms in U.S. Iraq and Afghanistan-Era Veterans: Implications for Biomarkers and Therapeutics. Pain Med. 2016, 17, 25–32. [Google Scholar] [CrossRef]
  416. Marx, C.E.; Naylor, J.C.; Kilts, J.D.; Dunn, C.E.; Tupler, L.A.; Szabo, S.T.; Capehart, B.P.; Morey, R.A.; Shampine, L.J.; Acheson, S.K. Neurosteroids and Traumatic Brain Injury: Translating Biomarkers to Therapeutics; Overview and Pilot Investigations in Iraq and Afghanistan Era Veterans. In Translational Research in Traumatic Brain Injury; Laskowitz, D., Grant, G., Eds.; Frontiers in Neuroscience; CRC Press/Taylor and Francis Group: Boca Raton, FL, USA, 2016. [Google Scholar]
  417. Naylor, J.C.; Kilts, J.D.; Shampine, L.J.; Parke, G.J.; Wagner, H.R.; Szabo, S.T.; Smith, K.D.; Allen, T.B.; Telford-Marx, E.G.; Dunn, C.E.; et al. Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain among US Military Veterans: A Randomized Clinical Trial. JAMA Netw. Open 2020, 3, e200287. [Google Scholar] [CrossRef]
  418. Ludvigsson, P.; Hesdorffer, D.; Olafsson, E.; Kjartansson, O.; Hauser, W.A. Migraine with aura is a risk factor for unprovoked seizures in children. Ann. Neurol. 2006, 59, 210–213. [Google Scholar] [CrossRef]
  419. Hillbom, M.; Pieninkeroinen, I.; Leone, M. Seizures in alcohol-dependent patients: Epidemiology, pathophysiology and management. CNS Drugs 2003, 17, 1013–1030. [Google Scholar] [CrossRef]
  420. Berg, A.T.; Plioplys, S. Epilepsy and autism: Is there a special relationship? Epilepsy Behav. 2012, 23, 193–198. [Google Scholar] [CrossRef]
  421. Seidenberg, M.; Pulsipher, D.T.; Hermann, B. Association of epilepsy and comorbid conditions. Future Neurol. 2009, 4, 663–668. [Google Scholar] [CrossRef]
  422. Reddy, D.S.; Kulkarni, S.K. Proconvulsant effects of neurosteroids pregnenolone sulfate and dehydroepiandrosterone sulfate in mice. Eur. J. Pharmacol. 1998, 345, 55–59. [Google Scholar] [CrossRef]
  423. Williamson, J.; Mtchedlishvili, Z.; Kapur, J. Characterization of the convulsant action of pregnenolone sulfate. Neuropharmacology 2004, 46, 856–864. [Google Scholar] [CrossRef]
  424. Bäckström, T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol. Scand. 1976, 54, 321–347. [Google Scholar] [CrossRef]
  425. Herzog, A.G.; Klein, P.; Ransil, B.J. Three patterns of catamenial epilepsy. Epilepsia 1997, 38, 1082–1088. [Google Scholar] [CrossRef]
  426. Najafi, M.; Sadeghi, M.M.; Mehvari, J.; Zare, M.; Akbari, M. Progesterone therapy in women with intractable catamenial epilepsy. Adv. Biomed. Res. 2013, 2, 8. [Google Scholar] [CrossRef]
  427. Kokate, T.G.; Banks, M.K.; Magoo, T.; Yamaguchi, S.-I.; Rogawski, M.A. Finasteride, a 5a-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice. J. Pharmacol. Exp. Ther. 1999, 288, 679–684. [Google Scholar]
  428. Bäckström, T.; Gee, K.W.; Lan, N.; Sörensen, M.; Wahlström, G. Steroids in relation to epilepsy and anaesthesia. In Ciba Foundation Symposium 153—Steroids and Neuronal Activity; Wiley: Hoboken, NJ, USA, 1990; pp. 225–230. [Google Scholar] [CrossRef]
  429. Nucera, B.; Rinaldi, F.; Dono, F.; Lanzone, J.; Evangelista, G.; Consoli, S.; Tappatà, M.; Narducci, F.; Troisi, S.; Trinka, E.; et al. Progesterone and its derivatives for the treatment of catamenial epilepsy: A systematic review. Seizure 2023, 109, 52–59. [Google Scholar] [CrossRef]
  430. Reddy, D.S. Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy. Front. Endocrinol. 2011, 2, 38. [Google Scholar] [CrossRef]
  431. Meng, J.; Yan, Z.; Tao, X.; Wang, W.; Wang, F.; Xue, T.; Liu, Y.; Wang, Z. The efficacy and safety of ganaxolone for the treatment of refractory epilepsy: A meta-analysis from randomized controlled trials. Epilepsia Open 2023, 8, 90–99. [Google Scholar] [CrossRef]
  432. Knight, E.M.P.; Amin, S.; Bahi-Buisson, N.; Benke, T.A.; Cross, J.H.; Demarest, S.T.; Olson, H.E.; Specchio, N.; Fleming, T.R.; Aimetti, A.A.; et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: Results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2022, 21, 417–427. [Google Scholar] [CrossRef]
  433. Olson, H.E.; Amin, S.; Bahi-Buisson, N.; Devinsky, O.; Marsh, E.D.; Pestana-Knight, E.; Rajaraman, R.R.; Aimetti, A.A.; Rybak, E.; Kong, F.; et al. Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up. Epilepsia 2024, 65, 37–45. [Google Scholar] [CrossRef]
  434. Costa, A.M.; Gol, M.; Lucchi, C.; Biagini, G. Antiepileptogenic effects of trilostane in the kainic acid model of temporal lobe epilepsy. Epilepsia 2023, 64, 1376–1389. [Google Scholar] [CrossRef]
  435. Gol, M.; Costa, A.M.; Biagini, G.; Lucchi, C. Seizure progression is slowed by enhancing neurosteroid availability in the brain of epileptic rats. Epilepsia 2024, 65, e41–e46. [Google Scholar] [CrossRef]
  436. Vezzani, A.; Aronica, E.; Mazarati, A.; Pittman, Q.J. Epilepsy and brain inflammation. Exp. Neurol. 2013, 244, 11–21. [Google Scholar] [CrossRef] [PubMed]
  437. Vargas-Sánchez, K.; Mogilevskaya, M.; Rodríguez-Pérez, J.; Rubiano, M.G.; Javela, J.J.; González-Reyes, R.E. Astroglial role in the pathophysiology of status epilepticus: An overview. Oncotarget 2018, 9, 26954–26976. [Google Scholar] [CrossRef]
  438. Wilcox, K.S.; Gee, J.M.; Gibbons, M.B.; Tvrdik, P.; White, J.A. Altered structure and function of astrocytes following status epilepticus. Epilepsy Behav. 2015, 49, 17–19. [Google Scholar] [CrossRef]
  439. Shen, Y.; Qin, H.; Chen, J.; Mou, L.; He, Y.; Yan, Y.; Zhou, H.; Lv, Y.; Chen, Z.; Wang, J.; et al. Postnatal activation of TLR4 in astrocytes promotes excitatory synaptogenesis in hippocampal neurons. J. Cell Biol. 2016, 215, 719–734. [Google Scholar] [CrossRef]
  440. Henneberger, C.; Steinhäuser, C. Astrocytic TLR4 at the crossroads of inflammation and seizure susceptibility. J. Cell Biol. 2016, 215, 607–609. [Google Scholar] [CrossRef]
  441. Yu, C.; Deng, X.-j.; Xu, D. Microglia in epilepsy. Neurobiol. Dis. 2023, 185, 106249. [Google Scholar] [CrossRef]
  442. Sano, F.; Shigetomi, E.; Shinozaki, Y.; Tsuzukiyama, H.; Saito, K.; Mikoshiba, K.; Horiuchi, H.; Cheung, D.L.; Nabekura, J.; Sugita, K.; et al. Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus. JCI Insight 2021, 6, e135391. [Google Scholar] [CrossRef]
  443. Çarçak, N.; Onat, F.; Sitnikova, E. Astrocytes as a target for therapeutic strategies in epilepsy: Current insights. Front. Mol. Neurosci. 2023, 16, 1183775. [Google Scholar] [CrossRef]
  444. Cartmell, T.; Luheshi, G.N.; Rothwell, N.J. Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat. J. Physiol. 1999, 518 Pt 2, 585–594. [Google Scholar] [CrossRef]
  445. Heida, J.G.; Pittman, Q.J. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia 2005, 46, 1906–1913. [Google Scholar] [CrossRef]
  446. Auvin, S.; Porta, N.; Nehlig, A.; Lecointe, C.; Vallée, L.; Bordet, R. Inflammation in rat pups subjected to short hyperthermic seizures enhances brain long-term excitability. Epilepsy Res. 2009, 86, 124–130. [Google Scholar] [CrossRef]
  447. Vezzani, A.; Baram, T.Z. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy Curr. 2007, 7, 45–50. [Google Scholar] [CrossRef]
  448. Vezzani, A.; Maroso, M.; Balosso, S.; Sanchez, M.A.; Bartfai, T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav. Immun. 2011, 25, 1281–1289. [Google Scholar] [CrossRef]
  449. von Rüden, E.-L.; Gualtieri, F.; Schönhoff, K.; Reiber, M.; Wolf, F.; Baumgärtner, W.; Hansmann, F.; Tipold, A.; Potschka, H. Molecular alterations of the TLR4-signaling cascade in canine epilepsy. BMC Vet. Res. 2020, 16, 18. [Google Scholar] [CrossRef]
  450. Liu, J.; Ke, P.; Guo, H.; Gu, J.; Liu, Y.; Tian, X.; Wang, X.; Xiao, F. Activation of TLR7-mediated autophagy increases epileptic susceptibility via reduced KIF5A-dependent GABA(A) receptor transport in a murine model. Exp. Mol. Med. 2023, 55, 1159–1173. [Google Scholar] [CrossRef]
  451. Wang, N.; Han, X.; Liu, H.; Zhao, T.; Li, J.; Feng, Y.; Mi, X.; Zhang, Y.; Chen, Y.; Wang, X. Myeloid differentiation factor 88 is up-regulated in epileptic brain and contributes to experimental seizures in rats. Exp. Neurol. 2017, 295, 23–35. [Google Scholar] [CrossRef]
  452. Wang, F.X.; Yang, X.L.; Ma, Y.S.; Wei, Y.J.; Yang, M.H.; Chen, X.; Chen, B.; He, Q.; Yang, Q.W.; Yang, H.; et al. TRIF contributes to epileptogenesis in temporal lobe epilepsy during TLR4 activation. Brain Behav. Immun. 2018, 67, 65–76. [Google Scholar] [CrossRef]
  453. di Biase, L.; Summa, S.; Tosi, J.; Taffoni, F.; Marano, M.; Cascio Rizzo, A.; Vecchio, F.; Formica, D.; Di Lazzaro, V.; Di Pino, G.; et al. Quantitative Analysis of Bradykinesia and Rigidity in Parkinson’s Disease. Front. Neurol. 2018, 9, 121. [Google Scholar] [CrossRef]
  454. Dzamko, N.; Gysbers, A.; Perera, G.; Bahar, A.; Shankar, A.; Gao, J.; Fu, Y.; Halliday, G.M. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol. 2017, 133, 303–319. [Google Scholar] [CrossRef]
  455. Drouin-Ouellet, J.; St-Amour, I.; Saint-Pierre, M.; Lamontagne-Proulx, J.; Kriz, J.; Barker, R.A.; Cicchetti, F. Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson’s disease. Int. J. Neuropsychopharmacol. 2014, 18, pyu103. [Google Scholar] [CrossRef]
  456. Nagatsu, T.; Mogi, M.; Ichinose, H.; Togari, A. Changes in cytokines and neurotrophins in Parkinson’s disease. J. Neural Transm. Suppl. 2000, 8, 277–290. [Google Scholar] [CrossRef]
  457. Cerri, S.; Mus, L.; Blandini, F. Parkinson’s Disease in Women and Men: What’s the Difference? J. Park. Dis. 2019, 9, 501–515. [Google Scholar] [CrossRef]
  458. Zirra, A.; Rao, S.C.; Bestwick, J.; Rajalingam, R.; Marras, C.; Blauwendraat, C.; Mata, I.F.; Noyce, A.J. Gender Differences in the Prevalence of Parkinson’s Disease. Mov. Disord. Clin. Pract. 2023, 10, 86–93. [Google Scholar] [CrossRef]
  459. Reekes, T.H.; Higginson, C.I.; Sigvardt, K.A.; King, D.S.; Levine, D.; Wheelock, V.L.; Disbrow, E.A. Sex differences in Parkinson disease-associated episodic memory and processing speed deficits. J. Int. Neuropsychol. Soc. 2023, 29, 813–820. [Google Scholar] [CrossRef]
  460. Shulman, L.M. Is there a connection between estrogen and Parkinson’s disease? Park. Relat. Disord. 2002, 8, 289–295. [Google Scholar] [CrossRef] [PubMed]
  461. Saunders-Pullman, R.; Gordon-Elliott, J.; Parides, M.; Fahn, S.; Saunders, H.R.; Bressman, S. The effect of estrogen replacement on early Parkinson’s disease. Neurology 1999, 52, 1417–1421. [Google Scholar] [CrossRef] [PubMed]
  462. di Michele, F.; Longone, P.; Romeo, E.; Lucchetti, S.; Brusa, L.; Pierantozzi, M.; Bassi, A.; Bernardi, G.; Stanzione, P. Decreased plasma and cerebrospinal fluid content of neuroactive steroids in Parkinson’s disease. Neurol. Sci. 2003, 24, 172–173. [Google Scholar] [CrossRef]
  463. Adeosun, S.O.; Hou, X.; Jiao, Y.; Zheng, B.; Henry, S.; Hill, R.; He, Z.; Pani, A.; Kyle, P.; Ou, X.; et al. Allopregnanolone reinstates tyrosine hydroxylase immunoreactive neurons and motor performance in an MPTP-lesioned mouse model of Parkinson’s disease. PLoS ONE 2012, 7, e50040. [Google Scholar] [CrossRef]
  464. Nezhadi, A.; Sheibani, V.; Esmaeilpour, K.; Shabani, M.; Esmaeili-Mahani, S. Neurosteroid allopregnanolone attenuates cognitive dysfunctions in 6-OHDA-induced rat model of Parkinson’s disease. Behav. Brain Res. 2016, 305, 258–264. [Google Scholar] [CrossRef]
  465. Castelnovo, L.F.; Thomas, P. Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor alpha (mPRalpha/PAQR7). Front. Endocrinol. 2023, 14, 1125962. [Google Scholar] [CrossRef] [PubMed]
  466. Litim, N.; Morissette, M.; Di Paolo, T. Effects of progesterone administered after MPTP on dopaminergic neurons of male mice. Neuropharmacology 2017, 117, 209–218. [Google Scholar] [CrossRef] [PubMed]
  467. Choe, M.A.; An, G.J.; Koo, B.S.; Jeon, S. Effect of DHEA on recovery of muscle atrophy induced by Parkinson’s disease. J. Korean Acad. Nurs. 2011, 41, 834–842. [Google Scholar] [CrossRef]
  468. Kumar, A.; Sidhu, J.; Goyal, A.; Tsao, J.W. Alzheimer Disease. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2024. [Google Scholar]
  469. Bard, F.; Cannon, C.; Barbour, R.; Burke, R.L.; Games, D.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 2000, 6, 916–919. [Google Scholar] [CrossRef]
  470. Bolmont, T.; Haiss, F.; Eicke, D.; Radde, R.; Mathis, C.A.; Klunk, W.E.; Kohsaka, S.; Jucker, M.; Calhoun, M.E. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J. Neurosci. 2008, 28, 4283–4292. [Google Scholar] [CrossRef] [PubMed]
  471. Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G.M.; Cooper, N.R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B.L.; et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging 2000, 21, 383–421. [Google Scholar] [CrossRef] [PubMed]
  472. Kinney, J.W.; Bemiller, S.M.; Murtishaw, A.S.; Leisgang, A.M.; Salazar, A.M.; Lamb, B.T. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement. 2018, 4, 575–590. [Google Scholar] [CrossRef] [PubMed]
  473. Chang, R.; Yee, K.L.; Sumbria, R.K. Tumor necrosis factor alpha Inhibition for Alzheimer’s Disease. J. Cent. Nerv. Syst. Dis. 2017, 9, 1179573517709278. [Google Scholar] [CrossRef] [PubMed]
  474. Forlenza, O.V.; Diniz, B.S.; Talib, L.L.; Mendonca, V.A.; Ojopi, E.B.; Gattaz, W.F.; Teixeira, A.L. Increased serum IL-1beta level in Alzheimer’s disease and mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 2009, 28, 507–512. [Google Scholar] [CrossRef] [PubMed]
  475. Blum-Degen, D.; Muller, T.; Kuhn, W.; Gerlach, M.; Przuntek, H.; Riederer, P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci. Lett. 1995, 202, 17–20. [Google Scholar] [CrossRef] [PubMed]
  476. Heneka, M.T.; Carson, M.J.; El Khoury, J.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015, 14, 388–405. [Google Scholar] [CrossRef]
  477. Djordjevic, J.; Sabbir, M.G.; Albensi, B.C. Traumatic Brain Injury as a Risk Factor for Alzheimer’s Disease: Is Inflammatory Signaling a Key Player? Curr. Alzheimer Res. 2016, 13, 730–738. [Google Scholar] [CrossRef]
  478. Sheng, J.G.; Zhu, S.G.; Jones, R.A.; Griffin, W.S.; Mrak, R.E. Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Exp. Neurol. 2000, 163, 388–391. [Google Scholar] [CrossRef]
  479. Chen, S.; Wang, J.M.; Irwin, R.W.; Yao, J.; Liu, L.; Brinton, R.D. Allopregnanolone promotes regeneration and reduces beta-amyloid burden in a preclinical model of Alzheimer’s disease. PLoS ONE 2011, 6, e24293. [Google Scholar] [CrossRef] [PubMed]
  480. Wang, J.M.; Singh, C.; Liu, L.; Irwin, R.W.; Chen, S.; Chung, E.J.; Thompson, R.F.; Brinton, R.D. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2010, 107, 6498–6503. [Google Scholar] [CrossRef] [PubMed]
  481. Singh, C.; Liu, L.; Wang, J.M.; Irwin, R.W.; Yao, J.; Chen, S.; Henry, S.; Thompson, R.F.; Brinton, R.D. Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Neurobiol. Aging 2012, 33, 1493–1506. [Google Scholar] [CrossRef]
  482. Hernandez, G.D.; Solinsky, C.M.; Mack, W.J.; Kono, N.; Rodgers, K.E.; Wu, C.Y.; Mollo, A.R.; Lopez, C.M.; Pawluczyk, S.; Bauer, G.; et al. Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer’s disease: A single and multiple ascending dose phase 1b/2a clinical trial. Alzheimers Dement. 2020, 6, e12107. [Google Scholar] [CrossRef]
  483. Paganini-Hill, A.; Henderson, V.W. Estrogen deficiency and risk of Alzheimer’s disease in women. Am. J. Epidemiol. 1994, 140, 256–261. [Google Scholar] [CrossRef] [PubMed]
  484. Kawas, C.; Resnick, S.; Morrison, A.; Brookmeyer, R.; Corrada, M.; Zonderman, A.; Bacal, C.; Lingle, D.D.; Metter, E. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: The Baltimore Longitudinal Study of Aging. Neurology 1997, 48, 1517–1521. [Google Scholar] [CrossRef]
  485. Carroll, J.C.; Rosario, E.R.; Chang, L.; Stanczyk, F.Z.; Oddo, S.; LaFerla, F.M.; Pike, C.J. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J. Neurosci. 2007, 27, 13357–13365. [Google Scholar] [CrossRef]
  486. Pan, X.; Wu, X.; Kaminga, A.C.; Wen, S.W.; Liu, A. Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate in Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Front. Aging Neurosci. 2019, 11, 61. [Google Scholar] [CrossRef]
  487. Kim, S.B.; Hill, M.; Kwak, Y.T.; Hampl, R.; Jo, D.H.; Morfin, R. Neurosteroids: Cerebrospinal fluid levels for Alzheimer’s disease and vascular dementia diagnostics. J. Clin. Endocrinol. Metab. 2003, 88, 5199–5206. [Google Scholar] [CrossRef]
  488. Wolkowitz, O.M.; Kramer, J.H.; Reus, V.I.; Costa, M.M.; Yaffe, K.; Walton, P.; Raskind, M.; Peskind, E.; Newhouse, P.; Sack, D.; et al. DHEA treatment of Alzheimer’s disease: A randomized, double-blind, placebo-controlled study. Neurology 2003, 60, 1071–1076. [Google Scholar] [CrossRef]
  489. Ouanes, S.; Clark, C.; Richiardi, J.; Marechal, B.; Lewczuk, P.; Kornhuber, J.; Kirschbaum, C.; Popp, J. Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate, Alzheimer’s Disease Pathology, and Cognitive Decline. Front. Aging Neurosci. 2022, 14, 892754. [Google Scholar] [CrossRef] [PubMed]
  490. Saleh, H.; Sadeghi, L. Investigation of THDOC effects on pathophysiological signs of Alzheimer’s disease as an endogenous neurosteroid: Inhibition of acetylcholinesterase and plaque deposition. Bratisl. Lek. Listy 2019, 120, 148–154. [Google Scholar] [CrossRef]
  491. Diagnostic and Statistical Manual of Mental Disorders: DSM-5™, 5th ed.; American Psychiatric Publishing, Inc.: Arlington, VA, USA, 2013.
  492. Robinson, D.P.; Klein, S.L. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm. Behav. 2012, 62, 263–271. [Google Scholar] [CrossRef] [PubMed]
  493. Sherer, M.L.; Posillico, C.K.; Schwarz, J.M. An examination of changes in maternal neuroimmune function during pregnancy and the postpartum period. Brain Behav. Immun. 2017, 66, 201–209. [Google Scholar] [CrossRef]
  494. Hirst, J.J.; Palliser, H.K.; Yates, D.M.; Yawno, T.; Walker, D.W. Neurosteroids in the fetus and neonate: Potential protective role in compromised pregnancies. Neurochem. Int. 2008, 52, 602–610. [Google Scholar] [CrossRef] [PubMed]
  495. Kelleher, M.A.; Hirst, J.J.; Palliser, H.K. Changes in neuroactive steroid concentrations after preterm delivery in the Guinea pig. Reprod. Sci. 2013, 20, 1365–1375. [Google Scholar] [CrossRef] [PubMed]
  496. Pang, R.; Mujuni, B.M.; Martinello, K.A.; Webb, E.L.; Nalwoga, A.; Ssekyewa, J.; Musoke, M.; Kurinczuk, J.J.; Sewegaba, M.; Cowan, F.M.; et al. Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes. Pediatr. Res. 2022, 92, 180–189. [Google Scholar] [CrossRef]
  497. Shaw, J.C.; Dyson, R.M.; Palliser, H.K.; Gray, C.; Berry, M.J.; Hirst, J.J. Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs. Pediatr. Res. 2019, 85, 86–96. [Google Scholar] [CrossRef] [PubMed]
  498. Zhao, H.; Zhang, H.; Liu, S.; Luo, W.; Jiang, Y.; Gao, J. Association of Peripheral Blood Levels of Cytokines with Autism Spectrum Disorder: A Meta-Analysis. Front. Psychiatry 2021, 12, 670200. [Google Scholar] [CrossRef] [PubMed]
  499. Di Marco, B.; Bonaccorso, C.M.; Aloisi, E.; D’Antoni, S.; Catania, M.V. Neuro-Inflammatory Mechanisms in Developmental Disorders Associated with Intellectual Disability and Autism Spectrum Disorder: A Neuro- Immune Perspective. CNS Neurol. Disord. Drug Targets 2016, 15, 448–463. [Google Scholar] [CrossRef]
  500. Vargas, D.L.; Nascimbene, C.; Krishnan, C.; Zimmerman, A.W.; Pardo, C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 2005, 57, 67–81. [Google Scholar] [CrossRef]
  501. Chew, L.; Sun, K.L.; Sun, W.; Wang, Z.; Rajadas, J.; Flores, R.E.; Arnold, E.; Jo, B.; Fung, L.K. Association of serum allopregnanolone with restricted and repetitive behaviors in adult males with autism. Psychoneuroendocrinology 2021, 123, 105039. [Google Scholar] [CrossRef]
  502. Ayatollahi, A.; Bagheri, S.; Ashraf-Ganjouei, A.; Moradi, K.; Mohammadi, M.R.; Akhondzadeh, S. Does Pregnenolone Adjunct to Risperidone Ameliorate Irritable Behavior in Adolescents with Autism Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial? Clin. Neuropharmacol. 2020, 43, 139–145. [Google Scholar] [CrossRef]
  503. Porcu, P.; O’Buckley, T.K.; Alward, S.E.; Marx, C.E.; Shampine, L.J.; Girdler, S.S.; Morrow, A.L. Simultaneous quantification of GABAergic 3alpha,5alpha/3alpha,5beta neuroactive steroids in human and rat serum. Steroids 2009, 74, 463–473. [Google Scholar] [CrossRef] [PubMed]
  504. VanDoren, M.J.; Matthews, D.B.; Janis, G.C.; Grobin, A.C.; Devaud, L.L.; Morrow, A.L. Neuroactive steroid 3α-hydroxy-5α-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol. J. Neurosci. 2000, 20, 1982–1989. [Google Scholar] [CrossRef] [PubMed]
  505. Porcu, P.; Sogliano, C.; Cinus, M.; Purdy, R.H.; Biggio, G.; Concas, A. Nicotine-induced changes in cerebrocortical neuroactive steroids and plasma corticosterone concentrations in the rat. Pharmacol. Biochem. Behav. 2003, 74, 683–690. [Google Scholar] [CrossRef]
  506. Concas, A.; Sogliano, C.; Porcu, P.; Marra, C.; Brundu, A.; Biggio, G. Neurosteroids in nicotine and morphine dependence. Psychopharmacology 2006, 186, 281–292. [Google Scholar] [CrossRef]
  507. Janak, P.H.; Redfern, J.E.M.; Samson, H.H. The reinforcing effects of ethanol are altered by the endogenous neurosteroid, allopregnanolone. Alcohol. Clin. Exp. Res. 1998, 22, 1106–1112. [Google Scholar] [CrossRef] [PubMed]
  508. Ford, M.M.; Nickel, J.D.; Phillips, T.J.; Finn, D.A. Neurosteroid modulators of GABA(A) receptors differentially modulate Ethanol intake patterns in male C57BL/6J mice. Alcohol. Clin. Exp. Res. 2005, 29, 1630–1640. [Google Scholar] [CrossRef]
  509. Ramaker, M.J.; Ford, M.M.; Fretwell, A.M.; Finn, D.A. Alteration of ethanol drinking in mice via modulation of the GABA(A) receptor with ganaxolone, finasteride, and gaboxadol. Alcohol. Clin. Exp. Res. 2011, 35, 1994–2007. [Google Scholar] [CrossRef]
  510. Ramaker, M.J.; Ford, M.M.; Phillips, T.J.; Finn, D.A. Differences in the reinstatement of ethanol seeking with ganaxolone and gaboxadol. Neuroscience 2014, 272, 180–187. [Google Scholar] [CrossRef] [PubMed]
  511. Boero, G.; McFarland, M.H.; Tyler, R.E.; O’Buckley, T.K.; Chery, S.L.; Robinson, D.L.; Besheer, J.; Morrow, A.L. Deleterious Interaction between the Neurosteroid (3alpha,5alpha)3-Hydroxypregnan-20-One (3alpha,5alpha-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats. Biomolecules 2023, 13, 1205. [Google Scholar] [CrossRef]
  512. Zamora-Sanchez, C.J.; Hansberg-Pastor, V.; Salido-Guadarrama, I.; Rodriguez-Dorantes, M.; Camacho-Arroyo, I. Allopregnanolone promotes proliferation and differential gene expression in human glioblastoma cells. Steroids 2017, 119, 36–42. [Google Scholar] [CrossRef] [PubMed]
  513. Zamora-Sánchez, C.J.; Bello-Alvarez, C.; Rodríguez-Dorantes, M.; Camacho-Arroyo, I. Allopregnanolone Promotes Migration and Invasion of Human Glioblastoma Cells through the Protein Tyrosine Kinase c-Src Activation. Int. J. Mol. Sci. 2022, 23, 4996. [Google Scholar] [CrossRef]
  514. Trabert, B.; Sherman, M.E.; Kannan, N.; Stanczyk, F.Z. Progesterone and Breast Cancer. Endocr. Rev. 2020, 41, 320–344. [Google Scholar] [CrossRef] [PubMed]
  515. Bello-Alvarez, C.; Camacho-Arroyo, I. Impact of sex in the prevalence and progression of glioblastomas: The role of gonadal steroid hormones. Biol. Sex. Differ. 2021, 12, 28. [Google Scholar] [CrossRef] [PubMed]
  516. Pelegrina, L.T.; de Los Angeles Sanhueza, M.; Ramona Caceres, A.R.; Cuello-Carrion, D.; Rodriguez, C.E.; Laconi, M.R. Effect of progesterone and first evidence about allopregnanolone action on the progression of epithelial human ovarian cancer cell lines. J. Steroid Biochem. Mol. Biol. 2020, 196, 105492. [Google Scholar] [CrossRef] [PubMed]
  517. Pang, Y.; Dong, J.; Thomas, P. Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors delta and epsilon (mPRdelta and mPRepsilon) and mPRdelta involvement in neurosteroid inhibition of apoptosis. Endocrinology 2013, 154, 283–295. [Google Scholar] [CrossRef] [PubMed]
  518. Costa, A.M.; Spence, K.T.; Smith, S.S.; ffrench-Mullen, J. Withdrawal from the endogenous steroid progesterone results in GABAA currents insensitive to benzodiazepine modulation in rat CA1 hippocampus. J. Neurophysiol. 1995, 74, 464–469. [Google Scholar] [CrossRef]
  519. Moran, M.H.; Smith, S.S. Progesterone withdrawal I: Pro-convulsant effects. Brain Res. 1998, 807, 84–90. [Google Scholar] [CrossRef]
  520. Moran, M.H.; Goldberg, N.; Smith, S.S. Progesterone withdrawal II: Insensitivity to the sedative effects of a benzodiazepine. Brain Res. 1998, 807, 91–100. [Google Scholar] [CrossRef] [PubMed]
  521. Smith, S.S.; Gong, Q.H.; Li, X.; Moran, M.H.; Bitran, D.; Frye, C.A.; Hsu, F. Withdrawal from 3alpha-OH-5alpha-pregnan-20-One using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor alpha4 subunit in association with increased anxiety. J. Neurosci. 1998, 18, 5275–5284. [Google Scholar] [CrossRef]
  522. Azhar, Y.; Din, A.U. Brexanolone. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2023. Available online: https://www.ncbi.nlm.nih.gov/books/NBK541054 (accessed on 10 January 2024).
  523. Miller, L.G.; Greenblatt, D.J.; Barnhill, J.G.; Shader, R.I. Chronic benzodiazepine administration I. Tolerance is associated with benzodiazepine receptor downregulation and decreased g-aminobutyric acidA receptor function. J. Pharmacol. Exp. Ther. 1988, 246, 170–176. [Google Scholar] [PubMed]
  524. Impagnatiello, F.; Pesold, C.; Longone, P.; Caruncho, H.; Fritschy, J.M.; Costa, E.; Guidotti, A. Modifications of g-aminobutyric acidA receptor subunit expression in rat neocortex during tolerance to diazepam. Mol. Pharmacol. 1996, 49, 822–831. [Google Scholar]
  525. Birzniece, V.; Turkmen, S.; Lindblad, C.; Zhu, D.; Johansson, I.M.; Backstrom, T.; Wahlstrom, G. GABA(A) receptor changes in acute allopregnanolone tolerance. Eur. J. Pharmacol. 2006, 535, 125–134. [Google Scholar] [CrossRef] [PubMed]
  526. Turkmen, S.; Backstrom, T.; Wahlstrom, G.; Andreen, L.; Johansson, I.M. Tolerance to allopregnanolone with focus on the GABA-A receptor. Br. J. Pharmacol. 2011, 162, 311–327. [Google Scholar] [CrossRef] [PubMed]
  527. Yu, R.; Follesa, P.; Ticku, M.K. Down-regulation of the GABA receptor subunits mRNA levels in mammalian cultured cortical neurons following chronic neurosteroid treatment. Brain Res. Mol. Brain Res. 1996, 41, 163–168. [Google Scholar] [CrossRef]
  528. Cornett, E.M.; Rando, L.; Labbe, A.M.; Perkins, W.; Kaye, A.M.; Kaye, A.D.; Viswanath, O.; Urits, I. Brexanolone to Treat Postpartum Depression in Adult Women. Psychopharmacol. Bull. 2021, 51, 115–130. [Google Scholar] [PubMed]
  529. Wang, S.; Zhang, W.; Liu, Z.; Zhang, T.; Wang, Y.; Li, W. Efficacy and safety of zuranolone in the treatment of major depressive disorder: A meta-analysis. Front. Neurosci. 2023, 17, 1332329. [Google Scholar] [CrossRef]
  530. Al-Harbi, K.S. Treatment-resistant depression: Therapeutic trends, challenges, and future directions. Patient Prefer. Adherence 2012, 6, 369–388. [Google Scholar] [CrossRef]
  531. Tranter, R.; O’Donovan, C.; Chandarana, P.; Kennedy, S. Prevalence and outcome of partial remission in depression. J. Psychiatry Neurosci. 2002, 27, 241–247. [Google Scholar] [PubMed]
  532. Sun, D.; Gao, W.; Hu, H.; Zhou, S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm. Sin. B 2022, 12, 3049–3062. [Google Scholar] [CrossRef] [PubMed]
  533. Hay, M.; Thomas, D.W.; Craighead, J.L.; Economides, C.; Rosenthal, J. Clinical development success rates for investigational drugs. Nat. Biotechnol. 2014, 32, 40–51. [Google Scholar] [CrossRef] [PubMed]
  534. O’Brien, P.L.; Thomas, C.P.; Hodgkin, D.; Levit, K.R.; Mark, T.L. The diminished pipeline for medications to treat mental health and substance use disorders. Psychiatr. Serv. 2014, 65, 1433–1438. [Google Scholar] [CrossRef]
  535. Mullard, A. Parsing clinical success rates. Nat. Rev. Drug Discov. 2016, 15, 477. [Google Scholar] [CrossRef]
  536. Van Norman, G.A. Phase II Trials in Drug Development and Adaptive Trial Design. JACC Basic Transl. Sci. 2019, 4, 428–437. [Google Scholar] [CrossRef] [PubMed]
  537. Pretorius, G.; Grignolo, A. Phase III trial failures: Costly, but preventable. Appl. Clin. Trials 2016, 25, 36–42. [Google Scholar]
  538. Arora, A.; Nain, P.; Kumari, R.; Kaur, J. Major causes associated with clinial trials failure and selective strategies to reduce these consequences: A Review. Arch. Pharm. Pract. 2021, 12, 45–53. [Google Scholar] [CrossRef]
  539. Zhu, T. Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer’s Perspective. Front. Psychiatry 2020, 11, 562660. [Google Scholar] [CrossRef]
  540. Norbury, A.; Seymour, B. Response heterogeneity: Challenges for personalised medicine and big data approaches in psychiatry and chronic pain. F1000Research 2018, 7, 55. [Google Scholar] [CrossRef]
  541. Shukla, A.K.; Jhaj, R.; Sadasivam, B. Brexanolone: Panacea for postpartum depression? Reply to: ‘Intravenous brexanolone for postpartum depression: What it is, how well does it work, and will it be used?’. Ther. Adv. Psychopharmacol. 2021, 11, 2045125321997293. [Google Scholar] [CrossRef]
  542. Nonacs, R. New Oral PPD Treatment Zuranolone Will Soon Hit the Market as Zurzuvae. 2023. Available online: https://womensmentalhealth.org/posts/zuranolone-or-zurzuvae-will-soon-hit-the-market/ (accessed on 10 January 2024).
  543. Kozhimannil, K.B.; Attanasio, L.B.; Hardeman, R.R.; O’Brien, M. Doula care supports near-universal breastfeeding initiation among diverse, low-income women. J. Midwifery Womens Health 2013, 58, 378–382. [Google Scholar] [CrossRef] [PubMed]
  544. Jin, Y.; Penning, T.M. Molecular docking simulations of steroid substrates into human cytosolic hydroxysteroid dehydrogenases (AKR1C1 and AKR1C2): Insights into positional and stereochemical preferences. Steroids 2006, 71, 380–391. [Google Scholar] [CrossRef]
  545. Wang, P.; Dang, L.; Zhu, B.T. Use of computational modeling approaches in studying the binding interactions of compounds with human estrogen receptors. Steroids 2016, 105, 26–41. [Google Scholar] [CrossRef]
  546. Mitchell, J. Small molecule immunosensing using surface plasmon resonance. Sensors 2010, 10, 7323–7346. [Google Scholar] [CrossRef] [PubMed]
  547. Cao, Y.; McDermott, M.T. A surface plasmon resonance based inhibition immunoassay for measurement of steroid hormones. Anal. Biochem. 2018, 557, 7–12. [Google Scholar] [CrossRef]
  548. Kumar, R. Cryo-EM technique and its application: Structure of steroid hormone receptors. Vitam. Horm. 2023, 123, 385–397. [Google Scholar] [CrossRef]
  549. Yi, P.; Yu, X.; Wang, Z.; O’Malley, B.W. Steroid receptor-coregulator transcriptional complexes: New insights from CryoEM. Essays Biochem. 2021, 65, 857–866. [Google Scholar] [CrossRef]
  550. Couture, J.-F.; Legrand, P.; Cantin, L.; Luu-The, V.; Labrie, F.; Breton, R. Human 20α–Hydroxysteroid Dehydrogenase: Crystallographic and Site-directed Mutagenesis Studies Lead to the Identification of an Alternative Binding Site for C21-steroids. J. Mol. Biol. 2003, 331, 593–604. [Google Scholar] [CrossRef]
  551. Loiarro, M.; Ruggiero, V.; Sette, C. Targeting TLR/IL-1R Signalling in Human Diseases. Mediat. Inflamm. 2010, 2010, 674363. [Google Scholar] [CrossRef] [PubMed]
  552. Luís, J.P.; Simões, C.J.V.; Brito, R.M.M. The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders. Int. J. Mol. Sci. 2022, 23, 1731. [Google Scholar] [CrossRef]
  553. Song, J.; Chen, D.; Pan, Y.; Shi, X.; Liu, Q.; Lu, X.; Xu, X.; Chen, G.; Cai, Y. Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury. Front. Pharmacol. 2021, 12, 775117. [Google Scholar] [CrossRef]
  554. Reddy, D.S.; Rogawski, M.A. Neurosteroids—Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy. In Jasper’s Basic Mechanisms of the Epilepsies; Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W., Delgado-Escueta, A.V., Eds.; National Center for Biotechnology Information: Bethesda, MD, USA, 2012. [Google Scholar]
  555. Martinez Botella, G.; Salituro, F.G.; Harrison, B.L.; Beresis, R.T.; Bai, Z.; Blanco, M.J.; Belfort, G.M.; Dai, J.; Loya, C.M.; Ackley, M.A.; et al. Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)(A) Receptor. J. Med. Chem. 2017, 60, 7810–7819. [Google Scholar] [CrossRef]
  556. Gasior, M.; Beekman, M.; Carter, R.B.; Goldberg, S.R.; Witkin, J.M. Antiepileptogenic effects of the novel synthetic neuroactive steroid, ganaxolone, against pentylenetetrazol-induced kindled seizures: Comparison with diazepam and valproate. Drug Dev. Res. 1998, 44, 21–33. [Google Scholar] [CrossRef]
  557. Yawno, T.; Miller, S.L.; Bennet, L.; Wong, F.; Hirst, J.J.; Fahey, M.; Walker, D.W. Ganaxolone: A New Treatment for Neonatal Seizures. Front. Cell. Neurosci. 2017, 11, 246. [Google Scholar] [CrossRef]
  558. Martinez Botella, G.; Salituro, F.G.; Harrison, B.L.; Beresis, R.T.; Bai, Z.; Shen, K.; Belfort, G.M.; Loya, C.M.; Ackley, M.A.; Grossman, S.J.; et al. Neuroactive Steroids. 1. Positive Allosteric Modulators of the (gamma-Aminobutyric Acid)A Receptor: Structure-Activity Relationships of Heterocyclic Substitution at C-21. J. Med. Chem. 2015, 58, 3500–3511. [Google Scholar] [CrossRef]
Figure 1. Neurosteroid biosynthesis and classification. Neurosteroid synthesis begins with the translocation of cholesterol into the mitochondria, where it is metabolized into pregnenolone by the cytochrome P450scc, a mitochondrial cholesterol side-chain cleavage enzyme (CYP11A1). Pregnenolone undergoes further conversions. It is transformed into progesterone by 3β-HSD 1/2 (3β-hydroxysteroid dehydrogenase). Progesterone can then be converted into 5α- or 5β-dihydroprogesterone (5α-DHP/5β-DHP) by 5α/β-reductase type I/II. 5α/β-DHP can be reduced to allopregnanolone (3α,5α-THP) or pregnanolone (3α,5β-THP) by the 3α-hydroxysteroid dehydrogenase III (3α-HSD) enzyme. Allopregnanolone can be reconverted into 5α-DHP or 5β-DHP. Progesterone can also be metabolized into 11-deoxycorticosterone (DOC) by the cytochrome P450 21-hydroxylase (CYP21A2), and further converted into 5α-dihydrodeoxycorticosterone (5α-DHDOC) or 5β-dihydrodeoxycorticosterone (5β-DHDOC) by the 5α- or 5β-reductases, respectively. 5α-DHDOC can be reduced into 3α,5α-THDOC (3α,5α-tetrahydro-deoxycorticosterone) and reconverted into 5α-DHDOC by the 3α-HSD enzyme. Likewise, 5β-DHDOC can be reduced into 3α,5β-THDOC (3α,5β-tetrahydrodeoxycorticosterone) and reconverted into 5β-DHDOC by the 3α-HSD enzyme. To form androstane steroids, pregnenolone can also be converted by the cytochrome P450-17A1 (CYP17A1) into 17OH-pregnanolone, then into dehydroepiandrosterone (DHEA). DHEA can be metabolized by 3β-HSD 1/2 into androstenedione, and then into estrone by the enzyme aromatase (CYP19A1). Estrone can be further converted into estradiol by 17β-HSD 1 (17β-hydroxysteroid dehydrogenase). Estradiol can be reconverted into estrone by 17β-HSD 2/4. The same enzyme, 17β-HSD 2/4, also converts DHEA into androstenediol (5-androstenediol, also known as androst-5-ene-3β,17β-diol; ADIOL). Androstenediol can be reconverted into DHEA by 17β-HSD 1 and further converted into testosterone by 3β-HSD 1/2. Moreover, androstenedione can be metabolized into testosterone by 17β-HSD 2 and reconverted into androstenedione by 17β-HSD 3/5. Alternatively, androstenedione can be converted to androstanedione by the 5α- or 5β-reductase enzymes and 3α-HSD to form 5α- or 5β-androsterone. Testosterone can be converted into estradiol by the aromatase (CYP19A1) or into dihydrotestosterone (5α-DHT or 5β-DHT) by the 5α- or 5β-reductase enzymes. Finally, 5α-DHT can be converted into androstanediol (3α-androstanediol also known as 5α-androstane-3α,17β-diol; 3α-diol) and reconverted into 5α-DHT by the 3α-HSD II/III enzymes. Pregnenolone and DHEA can also be converted into pregnenolone sulfate (PS) and DHEA sulfate (DHEAS) by the sulfatase enzyme and reconverted into pregnenolone and DHEA by removing the sulfate group with the sulfotransferase enzyme. Allopregnanolone, pregnanolone, 3α,5α- or 3α,5β-THDOC, 3α,5α- or 3α,5β-androsterone and 3α,5α- or 3α,5β-androstanediol all act as positive modulators of GABAA receptors; however, the pregnane derivatives have much higher affinity and potency than the androstane derivatives.
Figure 1. Neurosteroid biosynthesis and classification. Neurosteroid synthesis begins with the translocation of cholesterol into the mitochondria, where it is metabolized into pregnenolone by the cytochrome P450scc, a mitochondrial cholesterol side-chain cleavage enzyme (CYP11A1). Pregnenolone undergoes further conversions. It is transformed into progesterone by 3β-HSD 1/2 (3β-hydroxysteroid dehydrogenase). Progesterone can then be converted into 5α- or 5β-dihydroprogesterone (5α-DHP/5β-DHP) by 5α/β-reductase type I/II. 5α/β-DHP can be reduced to allopregnanolone (3α,5α-THP) or pregnanolone (3α,5β-THP) by the 3α-hydroxysteroid dehydrogenase III (3α-HSD) enzyme. Allopregnanolone can be reconverted into 5α-DHP or 5β-DHP. Progesterone can also be metabolized into 11-deoxycorticosterone (DOC) by the cytochrome P450 21-hydroxylase (CYP21A2), and further converted into 5α-dihydrodeoxycorticosterone (5α-DHDOC) or 5β-dihydrodeoxycorticosterone (5β-DHDOC) by the 5α- or 5β-reductases, respectively. 5α-DHDOC can be reduced into 3α,5α-THDOC (3α,5α-tetrahydro-deoxycorticosterone) and reconverted into 5α-DHDOC by the 3α-HSD enzyme. Likewise, 5β-DHDOC can be reduced into 3α,5β-THDOC (3α,5β-tetrahydrodeoxycorticosterone) and reconverted into 5β-DHDOC by the 3α-HSD enzyme. To form androstane steroids, pregnenolone can also be converted by the cytochrome P450-17A1 (CYP17A1) into 17OH-pregnanolone, then into dehydroepiandrosterone (DHEA). DHEA can be metabolized by 3β-HSD 1/2 into androstenedione, and then into estrone by the enzyme aromatase (CYP19A1). Estrone can be further converted into estradiol by 17β-HSD 1 (17β-hydroxysteroid dehydrogenase). Estradiol can be reconverted into estrone by 17β-HSD 2/4. The same enzyme, 17β-HSD 2/4, also converts DHEA into androstenediol (5-androstenediol, also known as androst-5-ene-3β,17β-diol; ADIOL). Androstenediol can be reconverted into DHEA by 17β-HSD 1 and further converted into testosterone by 3β-HSD 1/2. Moreover, androstenedione can be metabolized into testosterone by 17β-HSD 2 and reconverted into androstenedione by 17β-HSD 3/5. Alternatively, androstenedione can be converted to androstanedione by the 5α- or 5β-reductase enzymes and 3α-HSD to form 5α- or 5β-androsterone. Testosterone can be converted into estradiol by the aromatase (CYP19A1) or into dihydrotestosterone (5α-DHT or 5β-DHT) by the 5α- or 5β-reductase enzymes. Finally, 5α-DHT can be converted into androstanediol (3α-androstanediol also known as 5α-androstane-3α,17β-diol; 3α-diol) and reconverted into 5α-DHT by the 3α-HSD II/III enzymes. Pregnenolone and DHEA can also be converted into pregnenolone sulfate (PS) and DHEA sulfate (DHEAS) by the sulfatase enzyme and reconverted into pregnenolone and DHEA by removing the sulfate group with the sulfotransferase enzyme. Allopregnanolone, pregnanolone, 3α,5α- or 3α,5β-THDOC, 3α,5α- or 3α,5β-androsterone and 3α,5α- or 3α,5β-androstanediol all act as positive modulators of GABAA receptors; however, the pregnane derivatives have much higher affinity and potency than the androstane derivatives.
Life 14 00582 g001
Figure 2. The schematic model illustrates the inhibitory effects of allopregnanolone (3α,5α-THP) on toll-like receptor (TLR) inflammatory signaling pathways. Black line arrows represent TLR inflammatory pathways, while red X-shapes or arrows indicate the impacts of 3α,5α-THP. 3α,5α-THP inhibits the binding of TLR4 with both myeloid differentiation protein 2 (MD2) and myeloid differentiation primary response 88 (MyD88), as well as the α2 subunit protein of the gamma-aminobutyric acid A receptors. The binding of TLR2 and TLR7 with MyD88 is also inhibited by 3α,5α-THP (indicated by red X-shapes), preventing TLR pathway activation/initiation. Additionally, 3α,5α-THP promotes the degradation of TLR4 adapter toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) (indicated by red arrows). Consequently, these events lead to decreased levels of tumor necrosis factor receptor-associated factor 6 (TRAF6) and decreased activation of transforming growth factor beta-activated kinase 1 (TAK1), as evidenced by its decreased phosphorylation (indicated by a red arrow). The inhibition of TAK1 activation suppresses the activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinases 1/2 (ERK1/2), thereby inhibiting the activation of various transcription factors including cAMP response element-binding protein (CREB), signal transducer and activator of transcription 1 (STAT1) and activating transcription factor 2 (ATF2). Inhibition of TLR7/MyD88 signaling also involves the inhibition of interferon regulatory factor 7 (IRF7) activation. These events collectively result in the decline in inflammatory mediators including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and high mobility group box 1 protein (HMGB1). The schematic figure was created with BioRender.com.
Figure 2. The schematic model illustrates the inhibitory effects of allopregnanolone (3α,5α-THP) on toll-like receptor (TLR) inflammatory signaling pathways. Black line arrows represent TLR inflammatory pathways, while red X-shapes or arrows indicate the impacts of 3α,5α-THP. 3α,5α-THP inhibits the binding of TLR4 with both myeloid differentiation protein 2 (MD2) and myeloid differentiation primary response 88 (MyD88), as well as the α2 subunit protein of the gamma-aminobutyric acid A receptors. The binding of TLR2 and TLR7 with MyD88 is also inhibited by 3α,5α-THP (indicated by red X-shapes), preventing TLR pathway activation/initiation. Additionally, 3α,5α-THP promotes the degradation of TLR4 adapter toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) (indicated by red arrows). Consequently, these events lead to decreased levels of tumor necrosis factor receptor-associated factor 6 (TRAF6) and decreased activation of transforming growth factor beta-activated kinase 1 (TAK1), as evidenced by its decreased phosphorylation (indicated by a red arrow). The inhibition of TAK1 activation suppresses the activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinases 1/2 (ERK1/2), thereby inhibiting the activation of various transcription factors including cAMP response element-binding protein (CREB), signal transducer and activator of transcription 1 (STAT1) and activating transcription factor 2 (ATF2). Inhibition of TLR7/MyD88 signaling also involves the inhibition of interferon regulatory factor 7 (IRF7) activation. These events collectively result in the decline in inflammatory mediators including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and high mobility group box 1 protein (HMGB1). The schematic figure was created with BioRender.com.
Life 14 00582 g002
Figure 3. The schematic model illustrates how allopregnanolone (3α,5α-THP) induces endosomal toll/interleukin-1 receptor domain-containing adapter-inducing interferon-beta (TRIF)-dependent toll-like receptor 4 (TLR4) anti-inflammatory signaling, leading to elevated levels of interleukin-10 (IL-10). 3α,5α-THP facilitates the transition of TLR4 from the toll/interleukin-1 receptor (TIR) domain-containing adapter protein (TIRAP)-myeloid differentiation primary response 88 (MyD88)-associated plasma membrane complex to an endosomal TRIF-related adapter molecule (TRAM)-TRIF complex, initiating the activation of the endosomal anti-inflammatory TLR4-TRIF signal and subsequent IL-10 production. Mechanistically, 3α,5α-THP upregulates the p110δ isoform of phosphoinositide 3-kinase (PI3K), promoting the degradation of TIRAP and the release of TLR4 from the TIRAP-MyD88-associated plasma membrane complex, facilitating TLR4 translocation to endosomes. Additionally, 3α,5α-THP facilitates TRIF accumulation in endosomes. The release of TLR4 from the TIRAP-MyD88-associated plasma membrane complex may also result from direct 3α,5α-THP-induced inhibition of the binding between TLR4 and MyD88, and TLR4 and myeloid differentiation factor 2 (MD2). Furthermore, both the inhibition of binding and TIRAP degradation suppress inflammatory TLR4 pathway components, cytokines, and chemokines. 3α,5α-THP activates the anti-inflammatory endosomal TLR4-TRIF pathway by triggering an increase in phosphorylated TRAM, a specific marker for TLR4-TRIF pathway activation. The model also incorporates 3α,5α-THP-induced enhanced presence of transcription factor specificity protein 1 (SP1), leading to increased IL-10 production. Additionally, 3α,5α-THP upregulates brain-derived neurotrophic factor (BDNF) levels, potentially amplifying IL-10 production, and release. Furthermore, 3α,5α-THP stimulates the accumulation of endosomal Ras-related protein Rab7 (Rab7), which may significantly impact the equilibrium between pro-inflammatory and anti-inflammatory TLR4 signaling pathways. In the figure, an increase in protein levels is indicated by a green up-arrow, protein degradation by a blue X-shape, and inhibition of protein–protein binding by a red X-shape. The schematic figure was created with BioRender.com.
Figure 3. The schematic model illustrates how allopregnanolone (3α,5α-THP) induces endosomal toll/interleukin-1 receptor domain-containing adapter-inducing interferon-beta (TRIF)-dependent toll-like receptor 4 (TLR4) anti-inflammatory signaling, leading to elevated levels of interleukin-10 (IL-10). 3α,5α-THP facilitates the transition of TLR4 from the toll/interleukin-1 receptor (TIR) domain-containing adapter protein (TIRAP)-myeloid differentiation primary response 88 (MyD88)-associated plasma membrane complex to an endosomal TRIF-related adapter molecule (TRAM)-TRIF complex, initiating the activation of the endosomal anti-inflammatory TLR4-TRIF signal and subsequent IL-10 production. Mechanistically, 3α,5α-THP upregulates the p110δ isoform of phosphoinositide 3-kinase (PI3K), promoting the degradation of TIRAP and the release of TLR4 from the TIRAP-MyD88-associated plasma membrane complex, facilitating TLR4 translocation to endosomes. Additionally, 3α,5α-THP facilitates TRIF accumulation in endosomes. The release of TLR4 from the TIRAP-MyD88-associated plasma membrane complex may also result from direct 3α,5α-THP-induced inhibition of the binding between TLR4 and MyD88, and TLR4 and myeloid differentiation factor 2 (MD2). Furthermore, both the inhibition of binding and TIRAP degradation suppress inflammatory TLR4 pathway components, cytokines, and chemokines. 3α,5α-THP activates the anti-inflammatory endosomal TLR4-TRIF pathway by triggering an increase in phosphorylated TRAM, a specific marker for TLR4-TRIF pathway activation. The model also incorporates 3α,5α-THP-induced enhanced presence of transcription factor specificity protein 1 (SP1), leading to increased IL-10 production. Additionally, 3α,5α-THP upregulates brain-derived neurotrophic factor (BDNF) levels, potentially amplifying IL-10 production, and release. Furthermore, 3α,5α-THP stimulates the accumulation of endosomal Ras-related protein Rab7 (Rab7), which may significantly impact the equilibrium between pro-inflammatory and anti-inflammatory TLR4 signaling pathways. In the figure, an increase in protein levels is indicated by a green up-arrow, protein degradation by a blue X-shape, and inhibition of protein–protein binding by a red X-shape. The schematic figure was created with BioRender.com.
Life 14 00582 g003
Table 1. Effects of neurosteroids on neuropsychiatric disease outcomes. Abbreviations: 3α,5α-THDOC: 3α,5α-tetrahydrodeoxycorticosterone; 3α,5β-THP: (3α,5β)3-hydroxypregnan-20-one or 3α,5β-tetrahydroprogesterone or pregnanolone; ACTH: adrenocorticotropic hormone; AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale–Cognitive subscale; AEA: anandamide; AEF0117: 3β-(4-methoxybenzyloxy)pregn-5-en-20-one; AEs: adverse events; ASD: autism spectrum disorder; AUD: alcohol use disorder; BDI: Beck Depression Inventory; BPD: bipolar depression; BRMS: Bech–Rafaelsen Melancholia Scale; CDD: cyclin-dependent kinase-like 5; CGI-I: Clinical Global Impression–Improvement; CUD: cocaine use disorder ; DES: Differential Emotion Scale; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; EPDS: Edinburgh Postnatal Depression Scale; GAD-7: Generalized Anxiety Disorder 7-item Scale; GDS: Geriatric Depression Scale; HAD-D: Hospital Anxiety and Depression Scale–Depression; HRSD & HAM-D: Hamilton Rating Scale for Depression; HRSA: Hamilton Rating Scale for Anxiety; IDS-SR: Inventory of Depressive Symptomatology-Self Report; IL: interleukin; LPS: lipopolysaccharide; MADRS: Montgomery-Åsberg Depression Rating Scale; MoCA: Montreal Cognitive Assessment Test; MRI: magnetic resonance imaging; PHQ-9: Patient Health Questionnaire; RAVLT: Rey Auditory Verbal Learning Test; SAEs: serious adverse events; TLR: toll-like receptor; TMT: Trail Making Test-B; TNF: tumor necrosis factor; VAS: 10-point Visual Analog Scale; YMRS: Young Mania Rating Scale; y.o.: years old.
Table 1. Effects of neurosteroids on neuropsychiatric disease outcomes. Abbreviations: 3α,5α-THDOC: 3α,5α-tetrahydrodeoxycorticosterone; 3α,5β-THP: (3α,5β)3-hydroxypregnan-20-one or 3α,5β-tetrahydroprogesterone or pregnanolone; ACTH: adrenocorticotropic hormone; AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale–Cognitive subscale; AEA: anandamide; AEF0117: 3β-(4-methoxybenzyloxy)pregn-5-en-20-one; AEs: adverse events; ASD: autism spectrum disorder; AUD: alcohol use disorder; BDI: Beck Depression Inventory; BPD: bipolar depression; BRMS: Bech–Rafaelsen Melancholia Scale; CDD: cyclin-dependent kinase-like 5; CGI-I: Clinical Global Impression–Improvement; CUD: cocaine use disorder ; DES: Differential Emotion Scale; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; EPDS: Edinburgh Postnatal Depression Scale; GAD-7: Generalized Anxiety Disorder 7-item Scale; GDS: Geriatric Depression Scale; HAD-D: Hospital Anxiety and Depression Scale–Depression; HRSD & HAM-D: Hamilton Rating Scale for Depression; HRSA: Hamilton Rating Scale for Anxiety; IDS-SR: Inventory of Depressive Symptomatology-Self Report; IL: interleukin; LPS: lipopolysaccharide; MADRS: Montgomery-Åsberg Depression Rating Scale; MoCA: Montreal Cognitive Assessment Test; MRI: magnetic resonance imaging; PHQ-9: Patient Health Questionnaire; RAVLT: Rey Auditory Verbal Learning Test; SAEs: serious adverse events; TLR: toll-like receptor; TMT: Trail Making Test-B; TNF: tumor necrosis factor; VAS: 10-point Visual Analog Scale; YMRS: Young Mania Rating Scale; y.o.: years old.
DiseaseNeurosteroid /Dose/Route of AdministrationSubjects/Age/SexOutcomesReferences
Postpartum DepressionBrexanolone 5 mg/mL in 250 mg/mL sulfobutylether-β-cyclo-dextrin, 60 hs continuous intravenous infusion
(30 μg/kg per h (0–4 h); 60 μg/kg per h (4–24 h); 90 μg/kg per h (24–52 h); 60 μg/kg per h (52–56 h); 30 μg/kg per h (56–60 h).)
Women with PPD (n = 18), 24–41 years old (y.o.)Brexanolone infusion reduced whole blood cell TNF-α and IL-6 and these effects were correlated with HAM-D score improvement. Brexanolone infusion prevented LPS- and imiquimod-induced elevation of TNF-α, IL-1β and IL-6 in whole blood cells in vitro, indicating inhibition of TLR4 and TLR7 responses. Inhibition of TNF-α, IL-1β and IL-6 responses to both LPS and imiquimod were correlated with HAM-D score improvements. Brexanolone infusion led to significant increases in allopregnanolone and 3α,5α-THDOC levels, while causing decreases in 3α,5α-androsterone and 3α,5α-androstandiol levels. Pregnenolone and 3α,5β-THP levels remained unchanged following infusion. However, there was no observed correlation between the percentage change in steroid levels post-infusion and the improvement in HAM-D scores.Balan et al., 2023 [64]
Postpartum DepressionBrexanolone 5 mg/mL in 250 mg/mL sulfobutylether-β-cyclo-dextrin, 60 h continuous intravenous infusion
(30 μg/kg per h (0–4 h); 60 μg/kg per h (4–24 h); 90 μg/kg per h (24–52 h); 60 μg/kg per h (52–56 h); 30 μg/kg per h (56–60 h).
Women with PPD (n = 21), 18–45 y.o.Brexanolone was generally well tolerated in PPD patients. Improvement in depressive symptoms (HAM-D and MADRS scores) was observed up to 30 days after brexanolone treatment.Kanes et al., 2017 [63]
Postpartum DepressionBrexanolone 5 mg/mL in 250 mg/mL sulfobutylether-β-cyclo-dextrin, 60 h continuous intravenous infusion
(30 μg/kg per h (0–4 h); 60 μg/kg per h (4–24 h); 90 μg/kg per h (24–52 h); 60 μg/kg per h (52–56 h); 30 μg/kg per h (56–60 h).
Women with PPD (Study 1 n = 120; Study 2 n = 100), 18–45 y.o.Brexanolone was generally well tolerated in PPD patients. Common adverse effects included somnolence, dizziness and sedation in 30% of patients. Improvement in depressive symptoms (HAM-D total scores, HAM-D remission and CGI-I response) was observed up to 30 days after brexanolone treatment. No changes in GAD-7, EPDS or PHQ scores were noted.Meltzer-Brody et al., 2018 [62]
Postpartum DepressionBrexanolone 5 mg/mL in 250 mg/mL sulfobutylether-β-cyclo-dextrin, 60 h continuous intravenous infusion
(30 μg/kg per h (0–4 h); 60 μg/kg per h (4–24 h); 90 μg/kg per h (24–52 h); 60 μg/kg per h (52–56 h); 30 μg/kg per h (56–60 h).
Women with PPD (n = 16), 18–45 y.o.Brexanolone was well tolerated in PPD patients. Improvement in depressive symptoms (HAM-D scores) was observed up to 16 months after brexanolone treatment.Patterson et al., 2022 [65]
Postpartum DepressionZuranolone 30 mg, administered orally each evening for 2 weeks.Women with PPD (n = 150), 18–45 y.o.Zuranolone was well tolerated in PPD patients; however (one patient experienced a serious adverse effect (confusional state) and abandoned the trial. Improvement in depressive symptoms (HAM-D, MADRS and HRSA scores) up to 45 days after Zuranolone treatment.Deligiannidis et al., 2021 [359]
Major Depressive DisorderZuranolone 30 mg, administered orally each evening for 2 weeks.Men and women with MDD (n = 89), 18–65 y.o.Zuranolone was well tolerated in MDD patients.
Improvement in depressive symptoms (HAM-D and CGI-I scores) at day 15.
Gunduz-Bruce et al., 2019 [360]
Major Depressive DisorderTestosterone 50–1000 mg/day, administered for 4–144 weeksMen with MDD (n = 1890), 27–80 y.o.Testosterone was well tolerated in patients with MDD. Reduction in depressive symptoms (HDRS, BDI-I/BDI-II, MADRS, PHQ-9, GDS, BRMS or/and HADS-D scores) was observed.Walther et al., 2019 (Meta-analysis) [362]
Bipolar DepressionPregnenolone titrated to 500 mg/day, oral administration (100 mg/day for 1 week, 150 mg/day for 3 weeks, 500 mg/day for 8 weeks).Men and women with BPD (n = 80), 18–75 y.o.Pregnanolone was well tolerated in BPD patients.
Improvement in depressive symptoms (HRSD scores) was observed, but not in anxiety symptoms (HRSA scores) or manic behavior (YMRS scores). A significant depression remission rate in the IDS-SR.
Brown et al., 2014 [43]
Unipolar and Bipolar DepressionPregnenolone titrated to 100 mg/day for 8 weeks.Men and women with BPD I or II with episodes of MDD and history of SUD (n = 70), 17–70 y.o.Pregnenolone was well tolerated in BPD patients. A trend toward significance favoring pregnanolone was detected in depressive (HRSD scores), and manic symptoms (YMRS scores) at the end of the treatment (week 8). No significant effect was observed on the cognitive assessment (RAVLT scores, TMT and Stroop Test).Osuji et al., 2010 [45]
Cocaine Use Disorder Progesterone 400 mg/day, oral administration for 7 days.Men and women with CUD (n = 46), 35–50 y.o.Progesterone was found to be safe and well tolerated in CUD patients.
Increases in allopregnanolone and pregnanolone plasma levels were observed in all patients. No effects on the levels of pregnenolone, testosterone, androstanediol, or DHEA; however, testosterone and androstanediol levels were higher in men than in women.
Milivojevic et al., 2019 [59]
Cocaine Use DisorderAEF0117, an unmetabolized derivative of pregnenolone: 0.06 mg/day (Cohort I), 1 mg/day (Cohort II), oral administration for 6 days.Men and women with CUD (n = 29), 21–60 y.o.AEF0117 (1 mg/day) reduced the subjective effects of cannabis, as measured by the ‘Intoxication’ subscale and the ‘Felt Good Cannabis Effect’ item. AEF0117 also decreased cannabis self-administration, with the 1 mg/day dose showing a greater effect compared to the 0.06 mg/day dose. The sequence of AEF0117 administration impacted outcomes, with AEF0117 maintaining its effects even after a washout period of ≥14 days, likely due to its long elimination half-life. AEF0117 was safe and well tolerated, with no significant treatment-related SAEs. Any observed AEs were similar between the AEF0117 and placebo groups, except for one unrelated severe AE. There was no evidence to suggest that AEF0117 precipitated symptoms of cannabis withdrawal. AEF0117 did not produce significant changes in endocannabinoid levels compared to placebo, except for a slight increase in AEA levels with the lower dose (0.06 mg/day), which was likely not caused by AEF0117 administration. There were minor effects on certain mood ratings, but these did not seem to be clinically relevant and were likely influenced by individual sensitivity to AEF0117’s effects.Haney et al., 2023 [66]
Alcohol Use DisorderPregnenolone 300 mg/day or 500 mg/day, oral administration for 8 weeks.Men and women with AUD (n = 43), 18–65 y.o.Pregnenolone was well tolerated in AUD patients. Decreases in alcohol craving scores (stress- and cue-induced). Decrease in anxiety response to stress (VAS scores) in the 300 mg dose group. Normalization of the ACTH/cortisol ratio following stress or alcohol cue was observed at both doses. Normalization of heart rate (stress-induced), systolic blood pressure (stress- and cue-induced), and diastolic blood pressure was noted (cue-induced, only in the 300 mg dose group).Milivojevic et al., 2023 [61]
Alzheimer’s diseaseDHEA (50 mg per os) administered orally 2x/day for 6 months.Men and postmenopausal women with AD ≥55 y.o. Increased DHEA and DHEAS levels in serum.
No improvements in cognitive performance (ADAS-Cog scores).
Wolkowitz et al., 2003 [488]
Alzheimer’s diseaseIntravenous allopregnanolone 1x/week for 12 weeks (doses: 0.3–3 mL).Men and women with AD or probable AD ≥55 y.o.Allopregnanolone was safe and well tolerated in all participants, with no significant differences in adverse events between treatment arms. Allopregnanolone levels in plasma reached a Tmax at 30 min post-infusion (2, 4, and 6 mg doses) and returned to the lower limit of quantification 4 h post-infusion. No indicators of sedation were observed at lower doses of allopregnanolone (2 mg and 4 mg), but increased sedation was observed at higher doses (6–18 mg). After 12 weeks of treatment, there were no statistically significant differences among cohorts in cognitive assessments (ADAS-Cog score, MoCA total score, and Cogstate Brief Battery composite score). MRI imaging data showed no adverse outcomes of allopregnanolone treatment on hippocampal volume, with a trend suggesting decreased atrophy in allopregnanolone-treated participants.Hernandez et al., 2020 [482]
PainPregnenolone
titrated up to 500 mg/day, oral administration (0 mg/day for 1 week, 50 mg twice a day for 1 week, 150 mg twice a day for 1 week, 250 mg twice a day for 2 weeks).
Iraq- and Afghanistan-era male veterans 18–65 years old with chronic lower back pain. Pregnenolone was well tolerated, with minor adverse effects in subjects.
Decreased lower back pain intensity and interference scores following 4 weeks of treatments.
Increased levels of pregnenolone and allopregnanolone in serum.
Naylor et al., 2020 [417]
Autism Spectrum Disorder Pregnenolone
Titrated by weight:
20 to 45 kg, up to 2.5 mg/day (0.5 mg/day before sleep for 1 week. 0.5 mg weekly increases were used until 1 mg in the morning and 1.5 mg before sleep).
>45 kg, up to 3.5 mg/day.
A group received 100 mg twice a day.
36 males and 23 females (11–17 y.o.). Pregnenolone improved irritability, stereotypy, and hyperactivity in adolescents with ASD. No significant adverse effects were observed when comparing the different treatment groups to the placebo control.Ayatollahi et al., 2020 [502]
EpilepsyGanaxolone
33–63 mg/kg or 900–1800 mg three times a day, oral suspension.
88 patients (79.5% female) 2–19 y.o. with CDD.Ganaxolone treatments were safe and well tolerated with mild adverse effects.
Following 2 years of treatment, motor seizure intensity, duration, and frequency decreased.
Olson et al., 2024 [433]
Epilepsy 40 mg progesterone daily in second half of the cycle from 15th to 25th day, oral administration.38 patients 18–45 y.o. women with catamenial epilepsy.Treatments involving progesterone have shown promise in reducing seizure frequency in women with intractable catamenial epilepsy.Najafi et al., 2013 [426]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Balan, I.; Boero, G.; Chéry, S.L.; McFarland, M.H.; Lopez, A.G.; Morrow, A.L. Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders. Life 2024, 14, 582. https://doi.org/10.3390/life14050582

AMA Style

Balan I, Boero G, Chéry SL, McFarland MH, Lopez AG, Morrow AL. Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders. Life. 2024; 14(5):582. https://doi.org/10.3390/life14050582

Chicago/Turabian Style

Balan, Irina, Giorgia Boero, Samantha Lucenell Chéry, Minna H. McFarland, Alejandro G. Lopez, and A. Leslie Morrow. 2024. "Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders" Life 14, no. 5: 582. https://doi.org/10.3390/life14050582

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics