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.

Neuroactive hormones and personal growth: associations in Chilean adolescents (ages 12-25) with ovulatory dysfunction.

Introduction: Hormones produced by the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis are crucial for modulating central nervous system (CNS) function and development throughout a person's life. Disruptions in HPAG function can impact psychological development, particularly during adolescence-a period marked by psychological growth and the maturation of the HPAG axis. An early indicator of HPAG alterations is ovulatory dysfunction (OD), a common condition among adolescents. Methods: This study explored the associations between neuroactive hormones and personal growth in adolescents with OD. Female participants aged 12-25 years with OD were recruited, and assessments were conducted to profile their basic hormonal levels and various dimensions of individual development, including self-concept clarity, sense of coherence, self-esteem, perfectionism, self-control, and mood states. Results: Adolescents with OD (n = 117) had lower self-concept clarity and self-esteem compared to reference data. A significant portion of the sample displayed elevated levels of tension (71.25%), confusion (62.5%), fatigue (58.22%), and depression (52.6%). Self-esteem scores were negatively correlated with DHEAS (r = -0.224; p = 0.026) and glucose (r = -0.249; p = 0.010). Higher levels of free testosterone were associated with increased depression scores (coef = 0.2398; p = 0.002), whereas higher estradiol levels were linked to lower aggressiveness scores (coef = -0.0648; p = 0.001). Discussion: These findings indicate that hormonal imbalances in adolescents with OD could affect personal growth. Further research is needed to establish causal relationships between the variables considered.

The Emerging Role of Neurosteroids: Novel Drugs Brexanalone, Sepranolone, Zuranolone, and Ganaxolone in Mood and Neurological Disorders.

This review investigates the potential of neurosteroids, including brexanolone, zuranolone, sepranolone, and ganaxalone, as therapeutic agents for a range of mood and neurological disorders. Notably, these disorders encompass postpartum depression, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), epilepsy, and Alzheimer's disease. Brexanolone and zuranolone have emerged as frontrunners in the treatment of postpartum depression, offering rapid relief from debilitating symptoms. Their mechanism of action involves modulation of the gamma-aminobutyric acid (GABA) system, which plays a pivotal role in mood regulation. Clinical trials have demonstrated their efficacy, heralding a potential breakthrough in addressing this often-overlooked condition. In the context of PTSD and MDD, neurosteroids have demonstrated significant promise. Their positive allosteric modulation of GABA-A receptors translates into improved mood stabilization and reduced symptoms. This novel approach represents a departure from conventional treatments and could offer newfound hope for individuals grappling with these disorders. Beyond mood disorders, neurosteroids, especially ganaxalone, exhibit potential in the realm of epilepsy management. Ganaxalone's capacity to control seizures is attributed to its GABAergic activity, which helps restore the delicate balance of neurotransmission in epileptic brains. Moreover, neurosteroids have revealed neuroprotective properties in Alzheimer's disease models. By influencing the GABAergic system, they mitigate excitotoxicity, a hallmark of Alzheimer's pathology. This neuroprotection opens a novel avenue for slowing neurodegeneration, although further research and clinical validation are essential. In conclusion, this review underscores the substantial therapeutic promise of neurosteroids in mood and neurological disorders. Their modulation of the GABA system emerges as a central mechanism of action, emphasizing the importance of GABAergic signaling in these conditions. The path forward entails continued investigation and clinical trials to fully unlock the potential of neurosteroids, offering hope for enhanced treatments in these challenging clinical domains.

Inhibitory actions of potentiating neuroactive steroids in the human α1ß3γ2L GABAA receptor.

The γ-aminobutyric acid type A (GABAA) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3ß-hydroxy steroids inhibit while 3α-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the α1ß3γ2L GABAA receptor by the endogenous neurosteroid 3α-hydroxy-5ß-pregnan-20-one (3α5ßP) and the synthetic neuroactive steroid 3α-hydroxy-5α-androstane-17ß-carbonitrile (ACN). The receptors were expressed in Xenopus oocytes. All experiments were done using two-electrode voltage-clamp electrophysiology. In the presence of low concentrations of GABA, 3α5ßP and ACN potentiate the GABAA receptor. To reveal inhibition, we conducted the experiments on receptors activated by the combination of a saturating concentration of GABA and propofol to fully activate the receptors and mask potentiation, or on mutant receptors in which potentiation is ablated. Under these conditions, both steroids inhibited the receptor with IC50s of ~13 µM and maximal inhibitory effects of 70-90%. Receptor inhibition by 3α5ßP was sensitive to substitution of the α1TM2-2' residue, previously shown to ablate inhibition by pregnenolone sulfate. However, results of coapplication studies and the apparent lack of state dependence suggest that pregnenolone sulfate and 3α5ßP inhibit the GABAA receptor independently and through distinct mechanisms. Mutations to the neurosteroid binding sites in the α1 and ß3 subunits significantly, albeit weakly and incompletely, reduced inhibition by 3α5ßP and ACN. Significance Statement The heteromeric GABAA receptor is inhibited by sulfated steroids and 3ß-hydroxy steroids while 3α-hydroxy steroids are considered to potentiate the receptor. We show here that 3α-hydroxy steroids have inhibitory effects on the α1ß3γ2L receptor, which are observed in specific experimental settings and are expected to manifest under different physiological conditions.

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.

Neurosteroids in Glioma: A Novel Therapeutic Concept.

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.

Expanding the therapeutic potential of neuro(active)steroids: a promising strategy for hyperdopaminergic behavioral phenotypes.

Imbalances in dopamine activity significantly contribute to the pathophysiology of several neuropsychiatric disorders, including addiction, ADHD, schizophrenia, impulse control disorders, and Parkinson's Disease. Neuro(active)steroids, comprising endogenous steroids that finely modulate neuronal activity, are considered crucial regulators of brain function and behavior, with implications in various physiological processes and pathological conditions. Specifically, subclasses of Neuro(active)steroids belonging to the 5α reductase pathway are prominently involved in brain disorders characterized by dopaminergic signaling imbalances. This review highlights the neuromodulatory effects of Neuro(active)steroids on the dopamine system and related aberrant behavioral phenotypes. We critically appraise the role of pregnenolone, progesterone, and allopregnanolone on dopamine signaling. Additionally, we discuss the impact of pharmacological interventions targeting 5α reductase activity in neuropsychiatric conditions characterized by excessive activation of the dopaminergic system, ranging from psychotic (endo)phenotypes and motor complications to decision-making problems and addiction.

Prospecting for para-endogenous anxiolytics in the human microbiome: Some promising pathways.

The gut microbiome is a vast, variable, and largely unexplored component of human biology that sits at the intersection of heritable and environmental factors, and represents a rich source of novel chemistry that is already known to be compatible with the human body. This alone would make it a promising place to search for new therapeutics, but recent work has also identified gut microbiome abnormalities in patients with a number of psychiatric disorders, including anxiety disorders-suggesting that not only treatments, but cures may lie therein. Here, we'll discuss two known "para-endogenous" anxiolytics-γ-hydroxybutyrate and the neurosteroid allopregnanolone-which have recently been discovered to be produced by the microbiome.

Direct measurements of neurosteroid binding to specific sites on GABAA receptors.

BACKGROUND AND PURPOSE: Neurosteroids are allosteric modulators of GABAA currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABAA receptor. EXPERIMENTAL APPROACH: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABAAR, a chimeric receptor containing transmembrane domains of the α1-GABAA receptor. Tryptophan mutagenesis was used to identify specific interactions. KEY RESULTS: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3ß-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites. CONCLUSIONS AND IMPLICATIONS: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABAAR were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites.

Neuroactive steroids fluctuate with regional specificity in the central and peripheral nervous system across the rat estrous cycle.

Neuroactive steroids (i.e., sex steroid hormones and neurosteroids) are important physiological regulators of nervous function and potential neuroprotective agents for neurodegenerative and psychiatric disorders. Sex is an important component of such effects. However, even if fluctuations in sex steroid hormone level during the menstrual cycle are associated with neuropathological events in some women, the neuroactive steroid pattern in the brain across the ovarian cycle has been poorly explored. Therefore, we assessed the levels of pregnenolone, progesterone, and its metabolites (i.e., dihydroprogesterone, allopregnanolone and isoallopregnanolone), dehydroepiandrosterone, testosterone and its metabolites (i.e., dihydrotestosterone, 3α-diol and 17ß-estradiol) across the rat ovarian cycle to determine whether their plasma fluctuations are similar to those occurring in the central (i.e., hippocampus and cerebral cortex) and peripheral (i.e., sciatic nerve) nervous system. Data obtained indicate that the plasma pattern of these molecules generally does not fully reflect the events occurring in the nervous system. In addition, for some neuroactive steroid levels, the pattern is not identical between the two brain regions and between the brain and peripheral nerves. Indeed, with the exception of progesterone, all other neuroactive steroids assessed here showed peculiar regional differences in their pattern of fluctuation in the nervous system during the estrous cycle. These observations may have important diagnostic and therapeutic consequences for neuropathological events influenced by the menstrual cycle.

Current View on PPAR-α and Its Relation to Neurosteroids in Alzheimer's Disease and Other Neuropsychiatric Disorders: Promising Targets in a Therapeutic Strategy.

Peroxisome proliferator-activated receptors (PPARs) may play an important role in the pathomechanism/pathogenesis of Alzheimer's disease (AD) and several other neurological/neuropsychiatric disorders. AD leads to progressive alterations in the redox state, ion homeostasis, lipids, and protein metabolism. Significant alterations in molecular processes and the functioning of several signaling pathways result in the degeneration and death of synapses and neuronal cells, leading to the most severe dementia. Peroxisome proliferator-activated receptor alpha (PPAR-α) is among the processes affected by AD; it regulates the transcription of genes related to the metabolism of cholesterol, fatty acids, other lipids and neurotransmission, mitochondria biogenesis, and function. PPAR-α is involved in the cholesterol transport to mitochondria, the substrate for neurosteroid biosynthesis. PPAR-α-coding enzymes, such as sulfotransferases, which are responsible for neurosteroid sulfation. The relation between PPAR-α and cholesterol/neurosteroids may have a significant impact on the course and progression of neurodegeneration/neuroprotection processes. Unfortunately, despite many years of intensive studies, the pathogenesis of AD is unknown and therapy for AD and other neurodegenerative diseases is symptomatic, presenting a significant goal and challenge today. This review presents recent achievements in therapeutic approaches for AD, which are targeting PPAR-α and its relation to cholesterol and neurosteroids in AD and neuropsychiatric disorders.

Neurosteroids and translocator protein 18 kDa (TSPO) ligands as novel treatment options in depression.

Recently, the gamma-aminobutyric acid (GABA) system has come into focus for the treatment of anxiety, postpartum depression, and major depressive disorder. Endogenous 3α-reduced steroids such as allopregnanolone are potent positive allosteric modulators of GABAA receptors and have been known for decades. Current industry developments and first approvals by the U.S. food and drug administration (FDA) for the treatment of postpartum depression with exogenous analogues of these steroids represent a major step forward in the field. 3α-reduced steroids target both synaptic and extrasynaptic GABAA receptors, unlike benzodiazepines, which bind to synaptic receptors. The first FDA-approved 3α-reduced steroid for postpartum depression is brexanolone, an intravenous formulation of allopregnanolone. It has been shown to provide rapid relief of depressive symptoms. An orally available 3α-reduced steroid is zuranolone, which also received FDA approval in 2023 for the treatment of postpartum depression. Although a number of studies have been conducted, the efficacy data were not sufficient to achieve approval of zuranolone in major depressive disorder by the FDA in 2023. The most prominent side effects of these 3α-reduced steroids are somnolence, dizziness and headache. In addition to the issue of efficacy, it should be noted that current data limit the use of these compounds to two weeks. An alternative to exogenous 3α-reduced steroids may be the use of substances that induce endogenous neurosteroidogenesis, such as the translocator protein 18 kDa (TSPO) ligand etifoxine. TSPO has been extensively studied for its role in steroidogenesis, in addition to other functions such as anti-inflammatory and neuroregenerative properties. Currently, etifoxine is the only clinically available TSPO ligand in France for the treatment of anxiety disorders. Studies are underway to evaluate its antidepressant potential. Hopefully, neurosteroid research will lead to the development of fast-acting antidepressants.

Forty Years Searching for Neurosteroid Binding Sites on GABAA Receptors.

Brain inhibition is a vital process for controlling and sculpting the excitability of the central nervous system in healthy individuals. This level of control is provided over several timescales and involves the neurotransmitter GABA acting at inhibitory synapses to: rapidly inhibit neurons by activating the GABAA receptor; over a slower timescale, to tonically activate extrasynaptic GABAA receptors to provide a low level of background inhibition; and finally, to activate G-protein coupled GABAB receptors to control transmitter release by inhibiting presynaptic Ca2+ channels whilst providing postsynaptic inhibition via K+ channel activation. From this plethora of roles for GABA and its receptors, the GABAA receptor isoform is of major interest due to its dynamic functional plasticity, which in part, is due to being targeted by modulatory brain neurosteroids derived from sex and stress hormones. This family of neurosteroids can, depending on their structure, potentiate, activate and also inhibit the activity of GABAA receptors to affect brain inhibition. This review tracks the methods that have been deployed in probing GABAA receptors, and charts the sterling efforts made by several groups to locate the key neurosteroid binding sites that affect these important receptors. Increasing our knowledge of these binding sites will greatly facilitate our understanding of the physiological roles of neurosteroids and will help to advance their use as novel therapeutics to combat debilitating brain diseases.

Neurosteroids and their Therapeutic Potential: Remembering the Contribution of Dr. Sabina Luchetti, Netherlands Institute for Neuroscience, Amsterdam, Netherlands.

This article traces the career of Dr. Sabina Luchetti (1969-2021), a noted physician (medical doctor, specialized in Neurology at Tor Vergata University of Rome, Italy), a dedicated neuroscientist (Ph.D. in Neuroscience at Tor Vergata University and IRCCS Santa Lucia of Rome), and a member of a renowned Netherlands group (senior researcher at Professor Swaab Laboratory of the Netherlands Institute for Neuroscience, Amsterdam, Netherlands), working in the field of brain function and diseases. She is particularly involved in the study of natural compounds, such as neurosteroids and their biosynthetic pathways in neurodegenerative and neuroinflammation- related disorders, working on post-mortem human brains. This editorial outlines Dr. Luchetti's wide range of interests, discloses her superior fund of knowledge, and recollects her humanitarian spirit, all of which contribute to creating a great sense of belonging to any group of researchers whom she worked with. The impact of Dr. Luchetti's work will continue to be felt for many years. From the bench to the bedside, her work has indirectly contributed to shedding light on the neurosteroids' potential therapeutic effects, considering that neurosteroids and their analogues (some of which are over-the-counter) are now used to treat depression, epilepsy, and substance abuse disorders. Moreover, the potential therapeutic effects of allopregnanolone with respect to its capability to promote neuroregeneration and neuroprotection are a promising basis for future treatment of neurodegenerative diseases.

Insights into neurosteroids and their role in women with epilepsy.

Epilepsy, is a serious neurological condition, characterized by recurring, unprovoked seizures and affects over 50 million people worldwide. Epilepsy has an equal prevalence in males and females, and occurs throughout the life span. Women with epilepsy (WWE) present with unique challenges due to the cyclical fluctuation of sex steroid hormone concentrations during their life course. These shifts in sex steroid hormones and their metabolites are intricately intertwined with seizure susceptibility and affect epilepsy during the life course of women in a complex manner. Here we present a review encompassing neurosteroids-steroids that act on the brain regardless of their site of synthesis in the body; the role of neurosteroids in women with epilepsy through their life-course; exogenous neurosteroid trials; and future research directions. The focus of this review is on progesterone and its derived neurosteroids, given the extensive basic research that supports their role in modulating neuronal excitability.

Twenty-first century antiepileptic drugs. An overview of their targets and synthetic approaches.

The therapeutic use of the traditional drugs against epilepsy has been hindered by their toxicity and low selectivity. These limitations have stimulated the design and development of new generations of antiepileptic drugs. This review explores the molecular targets and synthesis of the antiepileptic drugs that have entered the market in the 21st century, with a focus on manufacturer synthesis.

Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.

Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.

Simultaneous Determination of Selected Steroids with Neuroactive Effects in Human Serum by Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Neuroactive steroids are a group of steroid molecules that are involved in the regulation of functions of the nervous system. The nervous system is not only the site of their action, but their biosynthesis can also occur there. Neuroactive steroid levels depend not only on the physiological state of an individual (person's sex, age, diurnal variation, etc.), but they are also affected by various pathological processes in the nervous system (some neurological and psychiatric diseases or injuries), and new knowledge can be gained by monitoring these processes. The aim of our research was to develop and validate a comprehensive method for the simultaneous determination of selected steroids with neuroactive effects in human serum. The developed method enables high throughput and a sensitive quantitative analysis of nine neuroactive steroid substances (pregnenolone, progesterone, 5α-dihydroprogesterone, allopregnanolone, testosterone, 5α-dihydrotestosterone, androstenedione, dehydroepiandrosterone, and epiandrosterone) in 150 µL of human serum by ultrahigh-performance liquid chromatography with tandem mass spectrometry. The correlation coefficients above 0.999 indicated that the developed analytical procedure was linear in the range of 0.90 nmol/L to 28.46 µmol/L in human serum. The accuracy and precision of the method for all analytes ranged from 83 to 118% and from 0.9 to 14.1%, respectively. This described method could contribute to a deeper understanding of the pathophysiology of various diseases. Similarly, it can also be helpful in the search for new biomarkers and diagnostic options or therapeutic approaches.

Developmental and adult stress: effects of steroids and neurosteroids.

In humans, exposure to early life adversity has profound implications for susceptibility to developing neuropsychiatric disorders later in life. Studies in rodents have shown that stress experienced during early postnatal life can have lasting effects on brain development. Glucocorticoids and sex steroids are produced in endocrine glands and the brain from cholesterol; these molecules bind to nuclear and membrane-associated steroid receptors. Unlike other steroids that can also be made in the brain, neurosteroids bind specifically to neurotransmitter receptors, not steroid receptors. The relationships among steroids, neurosteroids, and stress are multifaceted and not yet fully understood. However, studies demonstrating altered levels of progestogens, androgens, estrogens, glucocorticoids, and their neuroactive metabolites in both developmental and adult stress paradigms strongly suggest that these molecules may be important players in stress effects on brain circuits and behavior. In this review, we discuss the influence of developmental and adult stress on various components of the brain, including neurons, glia, and perineuronal nets, with a focus on sex steroids and neurosteroids. Gaining an enhanced understanding of how early adversity impacts the intricate systems of brain steroid and neurosteroid regulation could prove instrumental in identifying novel therapeutic targets for stress-related conditions.

The translocator protein 18kDa ligand etifoxine in the treatment of depressive disorders-a double-blind, randomized, placebo-controlled proof-of-concept study.

BACKGROUND: Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects. METHODS: This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime. The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10-20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg. DISCUSSION: This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders. TRIAL REGISTRATION: Clinical Trials Register (EudraCT number: 2021-006773-38 , registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099 , registration date: 23 January 2023).