Search Results (68)

Background/Objectives: The gut–brain axis and systemic metabolic dysregulation are increasingly implicated in Alzheimer’s disease (AD) pathogenesis. This study aimed to characterize gut microbiota and plasma metabolomic profiles associated with amyloid pathology and cognitive impairment in patients with mild cognitive impairment (MCI). Methods: A cross-sectional multi-omics baseline analysis was performed in 47 MCI patients enrolled in a randomized, double-blind, crossover dietary intervention trial (NCT05029765). Gut microbiota composition was assessed by 16S rRNA sequencing (n = 47), and plasma metabolomics by untargeted LC-MS/MS (n = 45 after exclusion of two PCA-defined metabolomic outliers). Patients were stratified according to plasma amyloid-beta 42/40 ratio (BA42/40) and ADAScog11 score, representing complementary biomarkers of amyloid burden and cognitive impairment, respectively. Results: Higher amyloid burden and worse cognitive performance were associated with significant gut microbiota alterations, including increased alpha diversity and distinct beta diversity profiles. Differential abundance analyses consistently showed enrichment of Bacteroides-associated taxa and Akkermansia, alongside depletion of short-chain fatty acid-producing genera such as Faecalibacterium, Blautia, and Phascolarctobacterium. Plasma metabolomics identified a coherent signature associated with elevated BA42/40, characterized by accumulation of secondary bile acid sulfates and depletion of sphingolipids, neuroactive steroids, and anti-inflammatory lipid mediators, including pregnenolone sulfate, resolvin E1, and anandamide. A valid OPLS-DA discriminant model was obtained for BA42/40, whereas no predictive model was achieved for ADAScog11. Critically, this dissociation, characterized by significant microbiota differences but no metabolomic separation for ADAScog11, is itself an informative finding, suggesting that gut microbiota dysbiosis and plasma metabolomic alterations are not equally coupled to both dimensions of MCI pathophysiology. Conclusions: MCI patients with greater amyloid pathology and cognitive impairment exhibited gut microbiota dysbiosis. However, metabolic associations were observed only for BA42/40, but not for ADAScog11. These findings provide a mechanistic framework for evaluating the impact of Mediterranean diet and probiotic interventions in the longitudinal phase of the trial. Full article

Background/Objectives: Dementia is a progressive, multifactorial neurodegenerative syndrome that poses a major public health challenge, with an increasing number of cases due to an aging population. Vitamin D (vitD) is crucial not only for bone and calcium homeostasis, but also as a neuroactive steroid that influences brain functions such as neurotransmission, neuroprotection and immunomodulation. Emerging evidence suggests that vitD deficiency may be a modifiable risk factor for the development of dementia. Thus, the aim of this review is to understand the possible role of vitD as a modifiable risk factor in the prevention of dementia. Methods: Research was conducted in the PubMed and Scopus databases using combinations of the MeSH terms ‘calcitriol’, ‘dementia’, ‘vitamin D receptors’, and ‘brain function’ for articles from 2014 until 2026. Results: The analysis of the 30 articles retrieved exhibited a significant association between vitD deficiency and an increased risk of dementia. Longitudinal studies and meta-analyses have indicated an increased risk of dementia and Alzheimer’s disease proportional to the severity of the deficit. A significant association with vascular dementia was also highlighted, with the risk increasing synergistically in the presence of hypertension. Conclusions: The evidence reviewed suggests that both vitD deficiency and insufficiency are strongly associated with increased risk of dementia, particularly Alzheimer’s disease and vascular dementia. Addressing vitD deficiency by maintaining adequate levels is proposed as a potentially effective preventive strategy against cognitive decline and dementia. Full article

Background: This study aimed to investigate the relationship between serum neuroactive steroids (NAS) and oxytocin and craving and psychosocial functioning in men diagnosed with methamphetamine use disorder (MUD). Methods: In this observational cross-sectional study, 40 men with MUD (PG) and 41 non-substance-use-disorder controls (CG) completed measures of emotion dysregulation (DERS-16), attachment (ECR-R), aggression (BPAQ), and suicidal ideation (BSS). PG additionally completed the Substance Craving Scale (SCS) and Addiction Profile Index (API). Serum allopregnanolone (ALLO), DHEAS, testosterone, 17β-estradiol (E2), and oxytocin were assayed. Results: The results indicated that the PG exhibited significantly higher scores than the CG across all psychological measures. Robust adjusted group effects were observed for DERS-16 (Model 1: F = 35.507, p < 0.001; Model 2: F = 18.225, p < 0.001) and trait anger (Model 1: F = 41.104, p < 0.001; Model 2: F = 16.732, p < 0.001). Notably, serum levels of ALLO, DHEAS, testosterone, E2, and oxytocin did not differ significantly between groups. However, hormonal measures were strongly intercorrelated within both groups (r ≈ 0.877–0.936, all p < 0.001). In the PG, craving demonstrated positive correlations with DHEAS (r = 0.384, p = 0.014), testosterone (r = 0.415, p = 0.008), E2 (r = 0.360, p = 0.023), and oxytocin (r = 0.350, p = 0.027). A multivariable model analyzing craving was statistically significant (R² = 0.350; F(3,36) = 6.474, p = 0.001), with composite hormonal factor (B = 2.390, p = 0.016) serving as an independent predictor, while API Excluding Craving(API-EC) (p = 0.094) and DERS-16 did not emerge as a significant factor (p = 0.056). In hormone-specific models controlling for API-EC and DERS-16, DHEAS (p = 0.012), testosterone (p = 0.007), oxytocin (p = 0.023), and E2 (p = 0.023) retained significance after false discovery rate (FDR) correction; ALLO did not (p = 0.055). Conclusions: Despite the absence of significant differences in peripheral NAS and oxytocin levels between groups, men with MUD exhibited pronounced psychosocial impairments. The craving experienced during inpatient treatment was primarily elucidated by an integrated endocrine profile. These findings underscore the necessity for larger longitudinal studies incorporating repeated hormonal assessments to further explore these relationships. Full article

Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood–brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS/MS) (hippocampus: n = 16 PG+, n = 27 PG−; multi-tissue subset: n = 6 PG+, n = 21 PG−). Our data revealed a “dual-fate” mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol/g). The brain functioned as a “metabolic sink”, passively accumulating metabolites generated in peripheral organs—such as 17-hydroxypregnanolone—despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced “metabolic segregation” within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile—combining metabolic segregation with active central buffering—defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites—several with previously established GABAergic and neuroprotective activity—without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model. Full article

Background/Objectives: Perinatal depression poses significant risks to maternal and fetal health, yet biomarkers for treatment response in the field remain limited. Given the overlap in symptoms with major depressive disorder (MDD) and the comparatively more vast MDD literature, identifying promising MDD biomarkers for treatment response and examining corresponding perinatal depression biomarkers can reveal translational opportunities. Methods: PUBMED searches were conducted for individual biomarkers and MDD and perinatal depression, as well as with treatment response to antidepressant pharmacological treatment and neuromodulation treatments. When available, evidence from meta-analyses and systematic reviews were preferentially summarized. Review: This narrative review presents the current evidence on MDD and perinatal depression treatment response biomarkers, including brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B), electroencephalography, event-related potentials, metabolomics, hypothalamic–pituitary–adrenal axis hormones, neuroimaging markers, inflammatory markers, and neuroactive steroids. Conclusions: Biomarker research in MDD yields insights on promising biomarkers for treatment response, including BDNF, S100B, theta band density and cordance, inflammatory markers IL-8, CRP, and TNF- α, and neuroactive steroids. Full article

Despite the substantial global impact of ischemic stroke, current therapeutic options remain limited and only partially effective. To advance neuroprotective strategies that could improve the safety and efficacy of existing treatments while preserving brain tissue, we synthesized and evaluated seven new nitrones (MC3, MC5, MC7) and oximes (MC1, MC2, MC4, MC6) derived from different neuroactive steroids—ethisterone (MC1–3), mifepristone (MC4–5) and stanolone (MC6–7)—in an in vitro model of cerebral ischemia. Overall, these derivatives exhibited neuroprotective and antioxidant effects superior to those of the reference compounds cholesteronitrone ChN2, α-tert-butyl nitrone (PBN) and N-acetylcysteine (NAC). Notably, nitrones showed greater neuroprotective, anti-necrotic, and antioxidant potency than their corresponding oximes, regardless of the degree of molecular conjugation. Among them, the stanolone-derived nitrone MC7, which lacks conjugated double bonds, displayed the most balanced and robust profile, consistently enhancing cell viability, reducing necrotic cell death, and suppressing superoxide anion production. Consequently, MC7 has been selected as a promising lead compound for further in vivo studies of cerebral ischemia. Full article

Sex and gender disparities have emerged as critical determinants of COVID-19 outcomes, with males exhibiting higher hospitalization and mortality rates than females. Sex steroids such as estradiol, progesterone, and testosterone have been proposed as modulators of these differences, given their known roles in inflammation, immune function, and vascular health. However, the precise hormonal mechanisms underlying COVID-19 severity, particularly among individuals with comorbid hypertension—a major risk factor for adverse outcomes—remain unclear. In this study, we investigated circulating levels of key sex hormones and their neuroactive metabolites in 116 hypertensive COVID-19 patients enrolled through an urban academic emergency department. Our findings revealed distinct sex-based hormonal profiles and associations with disease severity. Males exhibited higher serum estradiol and testosterone levels, while progesterone levels were significantly higher in postmenopausal females. Notably, hospitalized patients showed elevated estradiol and progesterone levels compared to non-hospitalized individuals, whereas ICU-admitted patients had significantly lower concentrations of all three hormones. A unique exception was ICU-admitted postmenopausal females, who exhibited increased serum testosterone levels relative to non-ICU females. Additionally, in males, elevated 3α-diol was associated with hospitalization and ICU admission, while lower allopregnanolone and estradiol levels correlated with hypoxia in males and females, respectively. These results highlight a dynamic, sex-specific hormonal response to COVID-19 progression in hypertensive individuals, suggesting early upregulation and late depletion of protective sex steroids. Understanding these patterns may improve clinical risk stratification and inform the development of sex-targeted therapeutic interventions for COVID-19 and related inflammatory conditions. Full article

Dehydroepiandrosterone (DHEA) and its sulfate ester form DHEAS, are multifunctional steroid hormones primarily produced in the adrenal cortex, with additional synthesis in peripheral tissues. DHEA/DHEAS serve as precursors to sex steroids and exhibit neuroprotective, anti-inflammatory, and immune-modulating effects. DHEA levels decline significantly with age, a phenomenon termed “adrenopause”, prompting interest in supplementation to mitigate age-related symptoms. Particularly in postmenopausal women, DHEA has shown potential benefits in treating genitourinary syndrome of menopause (GSM), including improved vaginal health, lubrication, and sexual function. While intravaginal DHEA appears effective and safer than systemic estrogen therapy, especially for women with estrogen sensitivity, results remain mixed for oral administration. DHEA and DHEAS exhibit diverse neuroactive properties through modulation of GABA-A, NMDA, and sigma-1 receptors. These neurosteroids contribute to neuroprotection, synaptic plasticity, and mood regulation. Altered DHEA/DHEAS levels have been implicated in neurodegenerative disorders and depression, with emerging evidence supporting their potential therapeutic value. In addition, DHEA plays a multifaceted role in aging-related physiological changes. It supports muscle anabolism, bone density maintenance, cardiovascular protection, and immune regulation. Though supplementation shows potential benefits, especially in conjunction with resistance training, results remain discrepant. Current evidence has revealed that the therapeutic effects of DHEA supplementation are inconsistent in different human systems among different studies. The diversity of results is mainly due to heterogeneous receptor distribution, various action pathways, and distinct tissue responses in different systems. Further research is needed to define its efficacy and dosage across various systems. Full article

Allopregnanolone (allo) and isoallopregnanolone (isoallo) are neuroactive steroid epimers that differ in hydroxyl orientation at carbon three. Allo is a potent GABA-A receptor agonist, while isoallo acts as an antagonist, influencing brain function through their interconversion. Their metabolism varies across brain regions due to enzyme distribution, with AKR1C1–AKR1C3 active in the brain and AKR1C4 restricted to the liver. In rats, AKR1C9 (liver) and AKR1C14 (intestine) perform similar roles. Beyond AKR1Cs, HSD17Bs regulate steroid balance, with HSD17B6 active in the liver, thyroid, and lung, while HSD17B10, a mitochondrial enzyme, influences metabolism in high-energy tissues. Our current data obtained using the GC-MS/MS platform show that allo and isoallo in rats undergo significant metabolic conversion, suggesting a regulatory role in neurosteroid action. High allo levels following isoallo injection indicate brain interconversion, while isoallo clears more slowly from blood and undergoes extensive conjugation. Metabolite patterns differ between brain and plasma—allo injection leads to 5α-DHP and isoallo production, whereas isoallo treatment primarily yields allo. Human plasma contains mostly sulfate/glucuronided steroids (2.4–6% non-sulfate/glucuronided), whereas male rats exhibit much higher free steroid levels (29–56%), likely due to the absence of zona reticularis. These findings highlight tissue-specific enzymatic differences, which may impact neurosteroid regulation and CNS disorders. Full article

Background: Freeze tolerance is an uncommon but highly effective strategy that allows certain vertebrates to survive prolonged exposure to subzero temperatures in a frozen, ischemic state. While past studies have characterized the metabolic and biochemical adaptations involved, including cryoprotectant accumulation and metabolic rate suppression, the contribution of post-transcriptional gene regulation by microRNAs (miRNAs) remains largely unexplored. This study investigated freeze-responsive miRNAs in cardiac tissue of the gray tree frog, Dryophytes versicolor, to better understand the molecular mechanisms that support ischemic survival and tissue preservation. Methods: Adult frogs were subjected to controlled freezing at −2.5 °C, and cardiac tissue was collected from frozen and control animals. Total RNA was extracted and analyzed via small RNA sequencing to identify differentially expressed miRNAs, followed by target gene prediction and KEGG pathway enrichment analysis. Results: A total of 3 miRNAs were differentially expressed during freezing, with significant upregulation of miR-93-5p and let-7b-5p and downregulation of miR-4485-3p. Predicted targets of upregulated miRNAs included genes involved in immune signaling pathways (e.g., cytokine–cytokine receptor interaction), steroid hormone biosynthesis, and neuroactive ligand–receptor interaction, suggesting suppression of energetically costly signaling processes. Downregulation of miRNAs targeting cell cycle, insulin signaling, and WNT pathways indicates possible selective preservation of cytoprotective and repair functions. Conclusion: Overall, these results suggest that D. versicolor employs miRNA-mediated regulatory networks to support metabolic suppression, maintain essential signaling, and prevent damage during prolonged cardiac arrest. This work expands our understanding of freeze tolerance at the molecular level and may offer insights into biomedical strategies for cryopreservation and ischemia–reperfusion injury. Full article

Although opioids are effective in treating pain, they cause serious side effects. The use of regional anesthesia, although effective in the perioperative period, may not be suitable if mobility and lack of numbness is desired. Hence, there is a clear need for novel pain therapies. Low-voltage activated (T-type) calcium channels (Ca_V3.2 isoform) could be a promising therapeutic target for the development of novel pain therapies. Indeed, our published findings suggest that novel neuroactive steroid (NAS) analogs that modulate the activity of Ca_V3.2 channels have unique anti-nociceptive properties. However, the concern with current NASs appears to be their hypnotic/sedative properties, thus potentially hindering the future development of NASs for novel pain therapies. Hence, we developed a new line of NASs that are effective blockers of neuronal Ca_V3.2 channels in pain pathways while having more favorable pharmacodynamic properties, i.e., lack of sedative/hypnotic side effects. We present two promising novel analogs of NASs—B372 ((3β,5α,17β)-3-Hydroxyandrostan-17-carbonitrile) and YX23 ((3β,5α,17β)-3-Methoxyestran-17-ol). Using an in vitro approach, we show that B372 and YX23 are effective in blocking Ca_V3.2 channels. Using an in vivo approach, we show that they are effective anti-nociceptives in wild-type but not Ca_V3.2 knock-out mice. Importantly, we show that they lack sedative/hypnotic effects. Full article

Background: Finasteride, a 5α-reductase inhibitor commonly prescribed for androgenetic alopecia, has been linked to persistent adverse effects after discontinuation, known as post-finasteride syndrome (PFS). Symptoms include neurological, psychiatric, sexual, and gastrointestinal disturbances. Emerging evidence suggests that PFS may involve disruption of sex steroid homeostasis, neuroactive steroid deficiency (notably allopregnanolone, ALLO), and gut–brain axis alterations. Objective: This study aimed to investigate the effects of finasteride withdrawal (FW) in a rat model and evaluate the potential protective effects of ALLO on gut and hypothalamic inflammation. Methods: Adult male Sprague Dawley rats were treated with finasteride for 20 days, followed by one month of drug withdrawal. A subgroup received ALLO treatment during the withdrawal. Histological, molecular, and biochemical analyses were performed on the colon and hypothalamus. Gut microbiota-derived metabolites and markers of neuroinflammation and blood–brain barrier (BBB) integrity were also assessed. Results: At FW, rats exhibited significant colonic inflammation, including a 4.3-fold increase in Mφ1 levels (p < 0.001), a 2.31-fold decrease in butyrate concentration (p < 0.01), and elevated hypothalamic GFAP and Iba-1 protein expression (+360%, p < 0.01 and +100%, p < 0.01, respectively). ALLO treatment rescued these parameters in both the colon and hypothalamus but only partially restored mucosal and BBB structural integrity, as well as the NF-κB/PPARγ pathway. Conclusions: This preclinical study shows that FW causes inflammation in both the gut and hypothalamus in rats. ALLO treatment helped reduce several of these effects. These results suggest ALLO could have a protective role and have potential as a treatment for PFS patients. Full article

Neuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone (EpiP) in wild-type mice using behavioral assessment of hypnosis (loss of righting reflex, LORR) and in vivo electrophysiological recordings. Specifically, local field potentials (LFPs) were recorded from the central medial thalamus (CMT) and electroencephalogram (EEG) signals were recorded from the barrel cortex. We found that EpiP-induced LORR exhibited clear sex differences, with females showing increased sensitivity. Spectral power analysis and thalamocortical (TC) and corticocortical (CC) phase synchronization further supported enhanced hypnotic susceptibility in female mice. Our findings reveal characteristic sex-dependent effects of EpiP on the synchronized electrical activity in both thalamus and cortex. These results support renewed exploration of endogenous NAS as clinically relevant anesthetic agents. Full article

Postpartum depression (PPD) remains a significant health concern worldwide. Both non-pharmacological and pharmacological treatments are available for patients with PPD; however, the standard approach involving selective serotonin reuptake inhibitors (SSRIs) and other antidepressants fails to provide a rapid response. This narrative review presents basic clinical and epidemiological data on PPD, summarizes currently used pharmacotherapies of PPD, highlights their limitations, and discusses new therapies based on a revised understanding of the disease’s pathogenesis. Numerous studies indicate that dysregulation of GABAergic neurotransmission, which may result from fluctuating levels of neuroactive steroids during pregnancy and the postpartum period, plays an important role in the complex pathology of PPD. Considering this, neuroactive steroids, which act as positive allosteric modulators of central GABA_A receptors (GABA_ARs), may offer new promising avenues for treating PPD. The first rapid-acting neurosteroid approved by the FDA to treat PPD in women is brexanolone, although its use is constrained by pharmacokinetic properties. The first oral neuroactive steroid-based antidepressant approved by the FDA for PPD is zuranolone. This review discusses the molecular mechanism of zuranolone action and the results of preclinical and clinical studies regarding the effectiveness and safety of the drug in treating PPD. Full article

Background/Objectives: Postpartum depression (PPD) affects approximately 10–20% of women during and after pregnancy, posing significant risks to maternal health, infant development, and family dynamics. Identifying modifiable risk factors is essential for prevention. Emerging evidence suggests that vitamin D, a neuroactive steroid hormone involved in neurotransmitter synthesis, neuroinflammation regulation, and calcium homeostasis, may play a protective role against mood disorders, including PPD. Methods: The search was conducted through a comprehensive search of the PubMed, Scopus, and Web of Science databases using a combination of Medical Subject Headings (MeSH) and free-text terms including “vitamin D”, “25-hydroxyvitamin D”, “deficiency”, “pregnancy”, “postpartum”, “depression”, “antenatal depression”, “maternal mental health”, and “perinatal mood disorders”. Results: Numerous observational studies and systematic review reports around the world reinforce the potential global relevance of vitamin D insufficiency. This study advances personalized and precision medicine approaches by emphasizing the importance of individualized screening for vitamin D deficiency during pregnancy and postpartum, enabling tailored interventions that could mitigate the risk of postpartum depression. Conclusions: In conclusion, while a definitive causal relationship between vitamin D deficiency and perinatal depression remains unproven, screening for vitamin D levels during pregnancy could serve as a low-risk intervention to support maternal mental health. Future research should focus on well designed, large-scale randomized trials and standardization of diagnostic criteria to clarify vitamin D’s role in preventing perinatal depression. Recognizing vitamin D status as a modifiable biomarker allows for targeted nutritional and pharmacological strategies to optimize maternal mental health. Full article