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The Effects of Neurosteroids on Neurological and Psychiatric Disorders
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The Effects of Neurosteroids on Neurological and Psychiatric Disorders

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Physiology and Pathology".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 8175

Special Issue Editor

Dr. Irina S. Balan

E-Mail Website
Guest Editor
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Building, CB 7178, Chapel Hill, NC 27599, USA
Interests: neurosteroids; neuroinflammation; inflammatory and anti-inflammatory signals; toll-like receptors; alcohol use disorders; postpartum depression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We invite your contributions to our Special Issue on 'Neurosteroids in Neurological and Psychiatric Disorders.' This research collection explores the therapeutic potential of neuroactive steroids in various neurological and psychiatric conditions, including depression, anxiety disorders, post-traumatic stress disorder, substance use disorders, neurodegenerative diseases, schizophrenia, seizure disorders, neurodevelopmental disorders, and neurological injuries. Neurosteroids have pleiotropic effects, regulating critical systems such as neurotransmission, neuroendocrine pathways, neuroinflammation, and the immune response. They also influence neuroplasticity, synaptic plasticity, and neurodevelopment while displaying neuroprotective and anti-inflammatory properties that hold promise for both the prevention and treatment of neurological and psychiatric disorders. We welcome contributions that delve into the mechanisms underlying neurosteroids’ effects, potentially leading to new treatment strategies. Discussion of the cautions and limitations of neurosteroid therapy is encouraged, recognizing the necessity for comprehensive clinical studies to unlock their full potential. Join us in advancing our understanding of neurosteroids' impact on human health and forging novel therapeutic interventions.

Dr. Irina S. Balan
Guest Editor

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Keywords

  • pregnane neurosteroids
  • androstane neurosteroids
  • sulfated neurosteroids
  • neuroactive steroids
  • neurological disorders
  • psychiatric disorders
  • therapeutic potential
  • neuroprotective properties
  • anti-inflammatory properties

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Published Papers (5 papers)

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Research

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10 pages, 1586 KiB  
Communication
Stability and Reliability of Repeated Plasma Pregnenolone Levels After Oral Pregnenolone Dosing in Individuals with Cocaine Use Disorder: Pilot Findings
by Huaze Gao, Zachary Magin, Nia Fogelman, Rajita Sinha, Gustavo A. Angarita and Verica Milivojevic
Life 2024, 14(11), 1483; https://doi.org/10.3390/life14111483 - 14 Nov 2024
Viewed by 728
Abstract
Substance use disorders (SUDs), including cocaine use disorder (CUD), have significant negative health risks and impose a substantial social burden, yet effective treatments are limited. Pregnenolone, a neuroactive steroid precursor, has been shown to reduce alcohol craving and normalize stress biology in individuals [...] Read more.
Substance use disorders (SUDs), including cocaine use disorder (CUD), have significant negative health risks and impose a substantial social burden, yet effective treatments are limited. Pregnenolone, a neuroactive steroid precursor, has been shown to reduce alcohol craving and normalize stress biology in individuals with CUD, but its clinical utility has been questioned due to limited data on bioavailability and the stability of blood levels in humans. Thus, this pilot study aimed to determine whether twice-daily oral pregnenolone (PREG) at 300 mg/day and 500 mg/day versus placebo in week two of PREG administration led to stable increased plasma pregnenolone levels in individuals with CUD. Seven treatment-seeking individuals with CUD, enrolled in an eight-week double-blind clinical trial, were randomized to receive placebo (n = 2) or pregnenolone at 300 mg/day (n = 3) or 500 mg/day (n = 2). For the first two weeks of the eight-week trial, participants were admitted to an inpatient Clinical Neuroscience Research Unit for repeated serial sampling of plasma pregnenolone concentrations over a 32.5 h period in week two of their inpatient stay while taking their assigned study drug under observation. Pregnenolone levels showed a significant main effect of the medication group (p = 0.039), with sustained higher levels in the 300 mg (p = 0.018) and 500 mg (p = 0.035) groups compared to placebo, and no significant difference between the two pregnenolone dosing groups. Moreover, correlation analyses showed that after observed study medication dosing on repeated sampling day 1, levels of pregnenolone were highly associated across time, with strong, positive correlations between time of dosing and 2 h (r = 0.80, p = 0.031), 4 h (r = 0.80, p = 0.031), 6 h (r = 0.86, p = 0.013), and 8 h post-dosing (r = 0.97, p < 0.001). These findings from this pilot study suggest that chronic twice-daily/“bis in die” (b.i.d.) oral administration of pregnenolone at both 300 mg/day and 500 mg/day achieved stable and reliable elevated plasma pregnenolone levels over 32.5 h in individuals with CUD, thereby supporting the good bioavailability of pregnenolone in these samples. These data indicate that twice-daily chronic dosing may overcome any potential concerns of poor bioavailability and rapid metabolism of pregnenolone in humans, and support further clinical investigations into pregnenolone’s role in the treatment of cocaine use disorders. Full article
(This article belongs to the Special Issue The Effects of Neurosteroids on Neurological and Psychiatric Disorders)
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21 pages, 3860 KiB  
Article
The Uncoupling Effect of 17β-Estradiol Underlies the Resilience of Female-Derived Mitochondria to Damage after Experimental TBI
by Olivia J. Kalimon, Hemendra J. Vekaria, Paresh Prajapati, Sydney L. Short, W. Brad Hubbard and Patrick G. Sullivan
Life 2024, 14(8), 961; https://doi.org/10.3390/life14080961 - 30 Jul 2024
Viewed by 1060
Abstract
Current literature finds females have improved outcomes over their male counterparts after severe traumatic brain injury (TBI), while the opposite seems to be true for mild TBI. This begs the question as to what may be driving these sex differences after TBI. Estrogen [...] Read more.
Current literature finds females have improved outcomes over their male counterparts after severe traumatic brain injury (TBI), while the opposite seems to be true for mild TBI. This begs the question as to what may be driving these sex differences after TBI. Estrogen is thought to be neuroprotective in certain diseases, and its actions have been shown to influence mitochondrial function. Mitochondrial impairment is a major hallmark of TBI, and interestingly, this dysfunction has been shown to be more severe in males than females after brain injury. This suggests estrogen could be playing a role in promoting “mitoprotection” following TBI. Despite the existence of estrogen receptors in mitochondria, few studies have examined the direct role of estrogen on mitochondrial function, and no studies have explored this after TBI. We hypothesized ex vivo treatment of isolated mitochondria with 17β-estradiol (E2) would improve mitochondrial function after experimental TBI in mice. Total mitochondria from the ipsilateral (injured) and contralateral (control) cortices of male and female mice were isolated 24 h post-controlled severe cortical impact (CCI) and treated with vehicle, 2 nM E2, or 20 nM E2 immediately before measuring reactive oxygen species (ROS) production, bioenergetics, electron transport chain complex (ETC) activities, and β-oxidation of palmitoyl carnitine. Protein expression of oxidative phosphorylation (OXPHOS) complexes was also measured in these mitochondrial samples to determine whether this influenced functional outcomes with respect to sex or injury. While mitochondrial ROS production was affected by CCI in both sexes, there were other sex-specific patterns of mitochondrial injury 24 h following severe CCI. For instance, mitochondria from males were more susceptible to CCI-induced injury with respect to bioenergetics and ETC complex activities, whereas mitochondria from females showed only Complex II impairment and reduced β-oxidation after injury. Neither concentration of E2 influenced ETC complex activities themselves, but 20 nM E2 appeared to uncouple mitochondria isolated from the contralateral cortex in both sexes, as well as the injured ipsilateral cortex of females. These studies highlight the significance of measuring mitochondrial dysfunction in both sexes after TBI and also shed light on another potential neuroprotective mechanism in which E2 may attenuate mitochondrial dysfunction after TBI in vivo. Full article
(This article belongs to the Special Issue The Effects of Neurosteroids on Neurological and Psychiatric Disorders)
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Review

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20 pages, 3927 KiB  
Review
Impact of Sex Hormones on Glioblastoma: Sex-Related Differences and Neuroradiological Insights
by Jessica Rossi, Marialuisa Zedde, Manuela Napoli, Rosario Pascarella, Anna Pisanello, Giuseppe Biagini and Franco Valzania
Life 2024, 14(12), 1523; https://doi.org/10.3390/life14121523 - 21 Nov 2024
Viewed by 863
Abstract
Glioblastoma (GBM) displays significant gender disparities, being 1.6 times more prevalent in men, with a median survival time of 15.0 months for males compared to 25.5 months for females. These differences may be linked to gonadal steroid hormones, particularly testosterone, which interacts with [...] Read more.
Glioblastoma (GBM) displays significant gender disparities, being 1.6 times more prevalent in men, with a median survival time of 15.0 months for males compared to 25.5 months for females. These differences may be linked to gonadal steroid hormones, particularly testosterone, which interacts with the androgen receptor (AR) to promote tumor proliferation. Conversely, estrogen (E2), progesterone (P4), and P4 metabolites exert more complex effects on GBM. Despite these insights, the identification of reliable hormonal tumor markers remains challenging, and studies investigating hormone therapies yield inconclusive results due to small sample sizes and heterogeneous tumor histology. Additionally, genetic, epigenetic, and immunological factors play critical roles in sex disparities, with female patients demonstrating increased O6-Methylguanine-DNA methyltransferase promoter methylation and greater genomic instability. These complexities highlight the need for personalized therapeutic strategies that integrate hormonal influences alongside other sex-specific biological characteristics in the management of GBM. In this review, we present the current understanding of the potential role of sex hormones in the natural history of GBM. Full article
(This article belongs to the Special Issue The Effects of Neurosteroids on Neurological and Psychiatric Disorders)
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13 pages, 1692 KiB  
Review
Neurosteroids in Glioma: A Novel Therapeutic Concept
by Ava Hogan and Melike Mut
Life 2024, 14(8), 975; https://doi.org/10.3390/life14080975 - 2 Aug 2024
Cited by 1 | Viewed by 1161
Abstract
Glioma, a diverse group of brain and spinal cord tumors arising from glial cells, is characterized by varying degrees of malignancy, with some types exhibiting highly aggressive behavior, rapid proliferation, and invasive growth patterns, posing significant therapeutic challenges. This review delves into the [...] Read more.
Glioma, a diverse group of brain and spinal cord tumors arising from glial cells, is characterized by varying degrees of malignancy, with some types exhibiting highly aggressive behavior, rapid proliferation, and invasive growth patterns, posing significant therapeutic challenges. This review delves into the complex interactions between glioma cells, neurotransmitters, and neurosteroids, emphasizing their potential as therapeutic targets. Key neurotransmitters, like glutamate and gamma-aminobutyric acid (GABA), play crucial roles in glioma growth, invasion, and treatment response. This review examines the involvement of neurosteroids in glioma biology and explores innovative therapeutic strategies targeting these systems. It encompasses the biosynthesis and mechanisms of neurosteroids, interactions between gliomas and neurotransmitters, the spatial distribution of neurosteroid synthesis in gliomas, the role of ion channels, hormonal influences, enzyme modulation, and the neuroimmune system in glioma progression. Additionally, it highlights the potential of neurosteroids to modulate these pathways for therapeutic benefit. Full article
(This article belongs to the Special Issue The Effects of Neurosteroids on Neurological and Psychiatric Disorders)
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62 pages, 2061 KiB  
Review
Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders
by Irina Balan, Giorgia Boero, Samantha Lucenell Chéry, Minna H. McFarland, Alejandro G. Lopez and A. Leslie Morrow
Life 2024, 14(5), 582; https://doi.org/10.3390/life14050582 - 30 Apr 2024
Cited by 6 | Viewed by 3436
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Effects of Neurosteroids on Neurological and Psychiatric Disorders)
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