Neurosteroid Levels Research Articles

Reduced Levels of Neurosteroids in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients.

Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on motor neuron degeneration. This single-center case-control study included 37 patients with amyotrophic lateral sclerosis (ALS) and 28 healthy controls. Cerebrospinal fluid (CSF) neurosteroid levels were quantified using liquid chromatography-electrospray tandem mass spectrometry and compared between the two cohorts. Neurosteroid concentrations have been correlated with neuroinflammation and neurodegeneration biomarkers detected through an automated immunoassay, along with disease features and progression. Pregnenolone, progesterone, allopregnanolone, pregnanolone, and testosterone levels were significantly lower in ALS patients' CSF compared to healthy controls. A significant inverse correlation was found between neurofilament and neurosteroid levels. Neurosteroid concentrations did not correlate with disease progression, phenotype, genotype, or survival prediction. Our study suggests the independence of the disease features and its progression, from the dysregulation of neurosteroids in ALS patients' CSF. This neurosteroid reduction may relate to disease pathogenesis or be a consequence of disease-related processes, warranting further research. The inverse correlation between neurosteroids and neurofilament levels may indicate a failure of compensatory neuroprotective mechanisms against neurodegeneration.

Neurosteroid Levels in GBA Mutated and Non-Mutated Parkinson's Disease: A Possible Factor Influencing Clinical Phenotype?

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids' serum levels in a cohort of Parkinson's Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher's exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn's test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention.

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

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.

Premenstrual syndrome: new insights into etiology and review of treatment methods.

Premenstrual syndrome (PMS) is a common disorder affecting women of reproductive age, with an estimated global prevalence of 47.8%, with severe symptoms occurring in 3-8%, significantly affecting daily functioning. GABA conductance and changes in neurosteroid levels, particularly allopregnanolone, are suspected to play a substantial role in the disorder's etiology. In this paper, we provide an overview of recent reports on the etiology and recognized therapeutic approaches, encompassing both pharmacological and non-pharmacological interventions. Our examination includes studies on SSRIs, hormonal agents, neurosteroids, supplementation, and therapeutic roles. We aim to determine the most favorable treatment regimen by comparing medication effects and alternative methods. The treatment of PMS is crucial for enhancing the quality of life for affected women. Medications used in PMS treatment should be individually selected to achieve the best therapeutic effect, considering the clinical situation of the patients.

Pogimdyminės depresijos gydymas neurosteroidais

Neurosteroids, such as allopregnanolone, are primarily synthesized substances in the central nervous system which influence processes occurring in the brain. Fluctuations in the levels of neurosteroids can result in an increased anxiety and heightened sensitivity. Significant reduction in neurosteroid synthesis usually occurs during the perimenstrual and postpartum periods when very low levels of progesterone are observed. It is believed that a lack of neurosteroids in the body is one of the main causes of postpartum depression. Postpartum depression (PPD) is a form of depression which develops in women during the postnatal period. Clinical studies have been conducted, and the results indicate that Brexanolone (a water-soluble formulation of allopregnanolone) is effective in treating postpartum depression. Based on the evaluation of the HAMD-17 depression scale, women with PGD who received injectable neurosteroid doses achieved remission from postpartum depression more effectively and quickly than those in the placebo group. Subsequent studies were also conducted with the tablet form of neurosteroids (Zuranolone), and the results similarly showed favorable outcomes for postpartum depression. Additionally, during treatment with both injectable and tablet forms of neurosteroids, there were relatively few and non-threatening side effects for patients. This suggests that the benefits of neurosteroids in treating PPD may outweigh the potential harm and should possibly be considered and incorporated into the European psychiatric practice.

Seizure progression is slowed by enhancing neurosteroid availability in the brain of epileptic rats.

Trilostane is a 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA-treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video-electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography-electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease-modifying effect in the brain of epileptic rats.

Zuranolone - synthetic neurosteroid in treatment of mental disorders: narrative review.

With each passing year, the number of people suffering from mental disorders grows at a disturbing speed. Neuroactive steroids are a new promising group of drugs with the potential for use in many diseases like postpartum depression, postnatal psychosis, major depression, insomnia, bipolar disorder, and Parkinson's tremor, due to their ability to modulate the activity of GABAA receptor. Neurosteroids are progesterone metabolites that are synthesized from cholesterol or steroid hormones in various brain regions. They regulate neuronal development, regeneration, and neurotransmission. They are implicated in mood disorders, anxiety disorders, schizophrenia, PTSD, and impulsive aggression. Neurosteroids have been studied for their potential to prevent or treat neurodegenerative diseases such as Alzheimer's disease and HIV-associated dementia. They can promote neurogenesis, neuronal survival, myelination, and memory function. They can also affect the growth and sensitivity of hormone-dependent brain tumors such as gliomas. Zuranolone, a newly registered neurosteroid drug has shown huge flexibility in both clinical and ambulatory treatment thanks to its pharmacokinetic traits, especially the possibility for oral administration, unlike its predecessor Brexanolone. Zuranolone is a synthetic positive allosteric modulator of the GABAA receptor that can be taken orally. The review aims to summarize the current knowledge on zuranolone as a novel neurosteroid drug for various mental disorders, especially for postpartum mental disorders for which this drug was meant originally. It covers studies indexed in the PubMed, Scopus, and Web of Science databases published since 2017. Keywords used in the search, as well as inclusion and exclusion criteria, are given in the aims and methodology section. The review explains the evidence for the role of neurosteroids, especially allopregnanolone, in the pathophysiology and treatment of postpartum depression. It discusses the mechanisms of neurosteroid action, the changes in neurosteroid levels during pregnancy and postpartum, and the clinical trials of brexanolone and zuranolone, two synthetic analogs of allopregnanolone, for postpartum depression. It provides an overview of the biosynthesis and metabolism of neurosteroids in the central and peripheral nervous system. Furthermore, it explains the different sources and pathways of neurosteroid production and the factors that influence their synthesis and regulation, such as stress, hormones, drugs, and genetic variations. The review also explores the potential relevance of neurosteroids for other psychiatric disorders, such as major depression, bipolar disorder, post-traumatic stress disorder (PTSD), schizophrenia, and premenstrual dysphoric disorder. Finally, it highlights the associations between neurosteroid levels and symptom severity and the effects of neurosteroid modulation on mood, cognition, and neuroplasticity.

DDDR-14. DEVELOPMENT OF A NOVEL CYP17A1-TARGETED INHIBITOR FOR GLIOBLASTOMA

Abstract Glioblastoma (GBM) is a highly aggressive and invasive brain tumor, resistant to current standard treatments, including temozolomide (TMZ) and radiotherapy. Despite these interventions, GBM's intrinsic drug resistance often renders it incurable, thus highlighting the dire need for novel therapeutic strategies. In this study, we used ultra-high pressure liquid chromatography-mass spectrometry to examine the levels of neurosteroids in tumor specimens from primary and recurrent GBM patients. This led to the discovery of differential expression patterns, most notably in androgen, including dehydroepiandrosterone and testosterone. Our results indicated androgen over-production weakens the GBM's sensitivity to TMZ by inducing post-translational modification of Sp1 protein, which aids in DNA repair. Interestingly, Sp1 activity is further enhanced by histone deacetylase (HDAC) 6, which in turn diminishes the DNA damage caused by TMZ. In addition, proteomic analysis revealed an overexpression of cytochrome (CYP) 17A1, particularly in recurrent GBM, which led us to hypothesize that a drug inhibiting both CYP17A1 and HDAC6 could potentially serve as a viable treatment for TMZ-resistant GBM. To validate this, the drug was tested in vitro on U87MG-R cells and patient-derived Pt#3 TMZ-resistant cells, demonstrating the therapeutic efficacy based on cell viability assays. In vivo testing in the TMZ-resistant GBM orthotopic mouse model also showed promising anti-tumor activity, with treated mice demonstrating increased survival times compared to controls. In conclusion, our findings suggest that this drug targeting both CYP17A1 and HDAC6 presents a potential breakthrough in GBM-targeted therapy, addressing the pervasive issue of TMZ resistance.

Quantitative and Qualitative Analysis of Neurotransmitter and Neurosteroid Production in Cerebral Organoids during Differentiation.

In the human brain, neurophysiological activity is modulated by the movement of neurotransmitters and neurosteroids. To date, the similarity between cerebral organoids and actual human brains has been evaluated using comprehensive multiomics approaches. However, a systematic analysis of both neurotransmitters and neurosteroids from cerebral organoids has not yet been reported. Here, we performed quantitative and qualitative assessments of neurotransmitters and neurosteroids over the course of cerebral organoid differentiation. Our multiomics approaches revealed that the expression levels of neurotransmitter-related proteins and RNA, including neurosteroids, increase as cerebral organoids mature. We also found that the electrophysiological activity of human cerebral organoids increases in tandem with the expression levels of both neurotransmitters and neurosteroids. Our study demonstrates that the expression levels of neurotransmitters and neurosteroids can serve as key factors in evaluating the maturity and functionality of human cerebral organoids.

Effect of Neurosteroids on Basal and Stress-Induced Oxytocin Secretion in Luteal-Phase and Pregnant Sheep.

Oxytocin (OT) is a neuropeptide synthesized in the hypothalamic nuclei that modulates both behavioral and reproductive functions, associated with the increased neurosteroid synthesis in the brain. Therefore, the present study tested the hypothesis that manipulation of central neurosteroid levels could affect oxytocin synthesis and release in non-pregnant and pregnant sheep under both basal and stressful conditions. In Experiment 1, luteal-phase sheep were subjected to a series of intracerebroventricular (icv.) infusions of allopregnanolone (AL, 4 × 15 μg/60 μL/30 min) for 3 days. In Experiment 2, pregnant animals (4th month) received a series of infusions of the neurosteroid synthesis blocker, finasteride (4 × 25 μg/60 μL/30 min), conducted for 3 days. In non-pregnant sheep AL alone was shown to differentially modulate OT synthesis in basal conditions, and strongly inhibit OT response to stress (p < 0.001). In contrast, in pregnant animals, basal and stress-induced OT secretion was significantly (p < 0.001) increased during finasteride infusion compared to controls. In conclusion, we showed that neurosteroids were involved in the control of OT secretion in sheep, particularly under stress and pregnancy conditions and are part of an adaptive mechanism which is responsible for protecting and maintaining pregnancy in harmful situations.

Human Microglia Synthesize Neurosteroids to Cope with Rotenone-Induced Oxidative Stress.

We obtained evidence that mouse BV2 microglia synthesize neurosteroids dynamically to modify neurosteroid levels in response to oxidative damage caused by rotenone. Here, we evaluated whether neurosteroids could be produced and altered in response to rotenone by the human microglial clone 3 (HMC3) cell line. To this aim, HMC3 cultures were exposed to rotenone (100 nM) and neurosteroids were measured in the culture medium by liquid chromatography with tandem mass spectrometry. Microglia reactivity was evaluated by measuring interleukin 6 (IL-6) levels, whereas cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After 24 h (h), rotenone increased IL-6 and reactive oxygen species levels by approximately +37% over the baseline, without affecting cell viability; however, microglia viability was significantly reduced at 48 h (p < 0.01). These changes were accompanied by the downregulation of several neurosteroids, including pregnenolone, pregnenolone sulfate, 5α-dihydroprogesterone, and pregnanolone, except for allopregnanolone, which instead was remarkably increased (p < 0.05). Interestingly, treatment with exogenous allopregnanolone (1 nM) efficiently prevented the reduction in HMC3 cell viability. In conclusion, this is the first evidence that human microglia can produce allopregnanolone and that this neurosteroid is increasingly released in response to oxidative stress, to tentatively support the microglia's survival.

Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids

Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. PMDD symptoms are hypothesized to be linked to an altered sensitivity to normal luteal phase levels of allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite. Moreover, the endogenous 3β-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotion processing in PMDD, but whether this is associated to serum levels of ALLO, ISO or their relative concentration is unknown. In the present study, subjects with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids, the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Participants with PMDD exhibited greater activity in brain regions which are part of emotion-processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotion processing networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD subjects and controls. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABAA-active neurosteroids.

Antiepileptogenic effects of trilostane in the kainic acid model of temporal lobe epilepsy.

Epileptogenesis after status epilepticus (SE) has a faster onset in rats treated to reduce brain levels of the anticonvulsant neurosteroid allopregnanolone with the 5α-reductase inhibitor finasteride; however, it still has to be evaluated whether treatments aimed at increasing allopregnanolone levels could result in the opposite effect of delaying epileptogenesis. This possibility could be tested using the peripherally active inhibitor of 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase trilostane, which has been shown repeatedly to increase allopregnanolone levels in the brain. Trilostane (50 mg/kg) was administered subcutaneously once daily for up to six consecutive days, starting 10min after intraperitoneal administration of kainic acid (15 mg/kg). Seizures were evaluated by video-electrocorticographic recordings for 70 days maximum, and endogenous neurosteroid levels were assessed by liquid chromatography-electrospray tandem mass spectrometry. Immunohistochemical staining was performed to evaluate the presence of brain lesions. Trilostane did not alter the latency of kainic acid-induced SE onset or its overall duration. When compared to the vehicle-treated group, rats receiving six daily trilostane injections presented a remarkable delay of the first spontaneous electrocorticographic seizure and subsequent tonic-clonic spontaneous recurrent seizures (SRSs). Conversely, rats treated with only the first trilostane injection during SE did not differ from vehicle-treated rats in developing the SRSs. Notably, trilostane did not modify neuronal cell densities or the overall damage in the hippocampus. In comparison to the vehicle group, repeated administration of trilostane significantly decreased the activated microglia morphology in the subiculum. As expected, allopregnanolone and other neurosteroid levels were remarkably increased in the hippocampus and neocortex of rats treated for 6 days with trilostane, but pregnanolone was barely detectable. Neurosteroids returned to basal levels after a week of trilostane washout. Overall, these results suggest that trilostane led to a remarkable increase in allopregnanolone brain levels, which was associated with protracted effects on epileptogenesis.

Erinacine S from Hericium erinaceus mycelium promotes neuronal regeneration by inducing neurosteroids accumulation.

Erinacines derived from Hericium erinaceus have been shown to possess various health benefits including neuroprotective effect against neurodegenerative diseases, yet the underlying mechanism remains unknown. Here we found that erinacine S enhances neurite outgrowth in a cell autonomous fashion. It promotes post-injury axon regeneration of PNS neurons and enhances regeneration on inhibitory substrates of CNS neurons. Using RNA-seq and bioinformatic analyses, erinacine S was found to cause the accumulation of neurosteroids in neurons. ELISA and neurosteroidogenesis inhibitor assays were performed to validate this effect. This research uncovers a previously unknown effect of erinacine S on raising the level of neurosteroids.

Brexanolone therapeutics in post-partum depression involves inhibition of systemic inflammatory pathways.

Brexanolone has rapid, long-lasting, and remarkable efficacy in the treatment of post-partum depression (PPD). We test the hypothesis that brexanolone inhibits proinflammatory modulators and macrophage activation in PPD patients, which may promote clinical recovery. PPD patients (N=18) provided blood samples before and after brexanolone infusion according to the FDA-approved protocol. Patients were unresponsive to prior treatment before brexanolone therapy. Serum was collected to determine neurosteroid levels and whole blood cell lysates were examined for inflammatory markers and invitro responses to the inflammatory activators lipopolysaccharide (LPS) and imiquimod (IMQ). Brexanolone infusion altered multiple neuroactive steroid levels (N=15-18), reduced levels of inflammatory mediators (N=11) and inhibited their response to inflammatory immune activators (N=9-11). Specifically, brexanolone infusion reduced whole blood cell tumor necrosis factor-α (TNF-α, p=0.003), and interleukin-6 (IL-6, p=0.04) and these effects were correlated with HAM-D score improvement (TNF-α, p=0.049; IL-6, p=0.02). Furthermore, brexanolone infusion prevented LPS and IMQ-induced elevation of TNF-α (LPS: p=0.02; IMQ: p=0.01), IL-1β (LPS: p=0.006; IMQ: p=0.02) and IL-6 (LPS: p=0.009; IMQ: p=0.01), indicating inhibition of toll-like receptor (TLR)4 and TLR7 responses. Finally, inhibition of TNF-α, IL-1β and IL-6 responses to both LPS and IMQ were correlated with HAM-D score improvements (p<0.05). Brexanolone actions involve inhibition of inflammatory mediator production and inhibition of inflammatory responses to TLR4 and TLR7 activators. The data suggest that inflammation plays a role in post-partum depression and that inhibition of inflammatory pathways contributes to the therapeutic efficacy of brexanolone. The Foundation of Hope, Raleigh, NC and UNC School of Medicine, Chapel Hill.

Barbiturates and pyrazolopyridines for the treatment of postpartum depression-repurposing of two drug classes.

Zulresso (brexanolone) is an aqueous formulation of the neurosteroid, allopregnanolone, and the only FDA-approved medication for the treatment of postpartum depression (PPD). While brexanolone is effective for the treatment of PPD, lengthy infusion time and high cost can be prohibitive. Failure of GABAA receptors to adapt to fluctuating neurosteroid levels is considered to predispose women to mood disorders in the postpartum period. Brexanolone is thought to act via stimulation of δ subunit-containing GABAA receptors, which are extrasynaptic and localized to particular brain regions. Neurosteroid stimulation of δ subunit-containing GABAA receptors leads to sustained inhibition (hyperpolarization) of GABAergic neurons, which makes δ subunit-containing GABAA receptors a potentially important pharmacologic target. Barbiturates and pyrazolopyridines are potent stimulators of δ subunit-containing GABAA receptors and therefore potentially cost-effective treatments for PPD. Barbiturates are often not prescribed, owing to risk of dependence and respiratory depression. The pyrazolopyridines were tested several decades ago for anxiety and depression but never developed commercially. Herein we use the FDA-approved dosing schedule of brexanolone and GABAA receptor binding data from various animal models to examine the safety, efficacy, and potential clinical utility of barbiturates and pyrazolopyridines for the treatment of PPD. We suggest consideration of repurposing barbiturates and pyrazolopyridines as safe and readily available treatment alternatives for PPD.

White Matter Microstructure Is Associated with Serum Neuroactive Steroids and Psychological Functioning.

Military service members are at increased risk for mental health issues, and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations among white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. ALLO is associated with whole-brain white matter FAT (β = 0.24, t = 3.05, p = 0.006). This association is significantly modulated by PTSD+mTBI comorbidity (β = 0.00, t = 2.50, p = 0.027), although an mTBI diagnosis alone did not significantly impact this association (p = 0.088). There was no significant association between PREGNE and FAT (p = 0.380). Importantly, lower FAT is associated with poor psychological functioning (β = -0.19, t = -2.35, p = 0.020). This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

Systematic analysis of the results of fundamental and clinical studies of ethifoxin

The main pharmacological use of etifoxine is the treatment of psychosomatic manifestations of anxiety. The purpose of this work is a systematic analysis of fundamental and clinical studies of etifoxine. In addition to the anxiolytic effect, which partially persists even after discontinuation of therapy, etifoxine is characterized by analgesic, neurotrophic and neuroprotective properties. Such a pharmacological profile of etifoxine is due not only to the activation of GABA receptors, but also to the effect on the levels of neurosteroids in the blood and in the brain. Modulation by etifoxine of neurosteroids' metabolism contributes to the manifestation of anxiolytic, anti-inflammatory, neuroprotective and other properties of etifoxine.

Low serum allopregnanolone levels in children with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) has increasing evidence for the role of neurohormones in its etiopathogenesis. It has been suggested that the effects of neurosteroids on the brain in the early developmental period may predispose to neurodevelopmental pathologies. In our study, we examined serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and allopregnanolone levels in children with ADHD and whether these neurosteroids differ in the presence of specific learning disorder (SLD) and oppositional defiant disorder (ODD) comorbidities (ADHD+SLD and ADHD+ODD). We also investigated the relationship between neurosteroid levels and the severity of ADHD symptoms. Thirty-five prepubertal children with ADHD and 33 prepubertal healthy children, all aged 6–10 years, were included in this study. The severity of ADHD symptoms was assessed with the parent-rated and teacher-rated Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S). Serum allopregnanolone levels were significantly lower in the ADHD group compared to healthy controls. When analyzed according to comorbidity status, serum allopregnanolone levels were lower in ADHD+SLD and ADHD+ODD groups compared to healthy controls. However, when compared to healthy children, serum DHEA and DHEA-S levels in children with ADHD were not significantly different. Serum allopregnanolone levels were negatively associated with teacher-rated T-DSM-IV-S hyperactivity/impulsivity scores for all participants only. These findings suggest that allopregnanolone may play a role in the pathophysiology of ADHD, especially in the presence of ODD and SLD comorbidities.

Ferulic acid inhibits catamenial epilepsy through modulation of female hormones.

Approximately 40% of women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. These seizures result from cyclic changes in circulating progesterone and estradiol levels and there is no effective treatment for this form of intractable epilepsy. We artificially increased progesterone levels and neurosteroid levels (pseudo-pregnancy) in adult Swiss albino female mice (19-23g) by injecting them with pregnant mares' serum gonadotropin (5 IU s.c.), followed by human chorionic gonadotropin (5 IU s.c.) after 46h. After this, ferulic acid (25, 50, 100mg/kg i.p.) treatment was given for 10 days. During treatment, progesterone, estradiol, and corticosterone levels were estimated in blood on days 1, 5, and 10. Neurosteroid withdrawal was induced by finasteride (50mg/kg, i.p.) on treatment day 9. Twenty-four hours after finasteride administration (day 10 of treatment), seizure susceptibility was evaluated with the sub-convulsant pentylenetetrazol (PTZ) dose (40mg/kg i.p.). Four to six hours after PTZ, animals were assessed for depression like phenotypes using tail-suspension test (TST). Four to six hours following TST, animals were euthanized, and discrete brain parts (cortex and hippocampus) were separated for estimation of norepinephrine, serotonin, and dopamine as well as glutamic acid decarboxylase (GAD) enzyme activity. PMSG and HCG treatment elevated progesterone and estradiol levels, assessed on days 1, 5, and 10 causing a state of pseudo-pregnancy. Treatment with finasteride increased seizure susceptibility and depression-like characteristics possibly due to decreased progesterone and elevated estrogen levels coupled with decreased monoamine and elevated corticosterone levels. Ferulic acid treatment, on the other hand, significantly decreased seizure susceptibility and depression like behavior, possibly because of increased progesterone, restored estradiol, corticosterone, monoamines, and GAD enzyme activity. We concluded anticonvulsant effect of ferulic acid in a mouse model of catamenial epilepsy, evidenced by favourable seizure attenuation and curative effect on the circulating progesterone, estradiol, and corticosterone levels along with restorative effect on GAD enzyme activity and monoamine levels.