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Neurosteroids in Neurological and Psychiatric Disorders: Therapeutic Implications.

Neurosteroids play a significant role in brain functions with substantial implications for mood regulation, seizure susceptibility, stress response, and potential therapeutic applications. However, dysregulation of steroidogenesis and its signalling is associated with various neurological and psychiatric disorders, such as major depressive disorder, schizophrenia, tourette syndrome and post-traumatic stress disorder, with altered levels of neuroactive steroids contributing to these conditions. Neurosteroids can counteract the effects of stress by enhancing GABAergic inhibition, thereby helping…

Neurosteroids and their role in sex-specific epilepsies.

Neurosteroids are involved in sex-specific epilepsies. Allopregnanolone and related endogenous neurosteroids in the brain control excessive neuronal excitability and seizure susceptibility. Neurosteroids activate GABA-A receptors, especially extrasynaptic αγδ-GABA-A receptor subtypes that mediate tonic inhibition and thus dampen network excitability. Our studies over the past decade have shown that neurosteroids are broad-spectrum anticonvulsants and confer seizure protection in various animal models. Neurosteroids also exert antiepileptogenic effects. There is emerging evidence on a critical …

Organizing actions of neurosteroids in the Purkinje neuron.

It is becoming clear that steroids can be synthesized de novo by the brain of vertebrates. Such steroids synthesized de novo in the brain, as well as other areas of the nervous system, are called neurosteroids. To understand neurosteroid actions in the brain, we need data on the specific biosynthesis in particular sites of the brain at particular times. Therefore our studies for this exciting area of neuroscience research have focused on the biosynthesis and action of neurosteroids in the identified neurosteroidogenic cells underlying important brain functions. We have demonstrated that the Pu…

Neurosteroids and early-life programming: An updated perspective.

Early-life stress can lead to detrimental offspring outcomes, including an increased risk for mood disorders and hypothalamic-pituitary-adrenal axis dysregulation. Neurosteroids bind to ligand-gated neurotransmitter receptors, rapidly modulating neuronal excitability and promoting termination of stress responses. Reduced neurosteroidogenesis underlies some of the aberrant neuroendocrine and behavioural phenotypes observed in adult prenatally stressed rodents. During development, disruptions in neurosteroid generation and action also lead to long-term programming effects on the off-spring's bra…

Sex differences in the anticonvulsant activity of neurosteroids.

Epilepsy is one of the leading causes of chronic neurological morbidity worldwide. Acquired epilepsy may result from a number of conditions, … show gender differences with female predominance or male predominance. Steroid hormones, endogenous neurosteroids, and sexually dimorphic neural networks appear to play a key role in sex differences in seizure susceptibility. Neurosteroids, such as allopregnanolone, reflect sex differences in their anticonvulsant activity. This Review provides a brief overview …

New biosynthesis and biological actions of avian neurosteroids.

De novo neurosteroidogenesis from cholesterol occurs in the brain of various avian species. However, the biosynthetic pathways leading to the formation of neurosteroids are still not completely elucidated. We have recently found that the avian brain produces 7α-hydroxypregnenolone, a novel bioactive neurosteroid that stimulates locomotor activity. Until recently, it was believed that neurosteroids are produced in neurons and glial cells in the central and peripheral nervous systems. However, our recent studies on birds have demonstrated that the pineal gland, an endocrine organ located close t…

Stress and neurosteroids in adult and aged rats.

The progesterone derivative 3 alpha-hydroxy-5 alpha-pregnan-20 one (allopregnanolone/AP) and the deoxycorticosterone derivative 3 alpha-21-dihydroxy-5 alpha- pregnan-20 one (allotetra-hydrodeoxycorticosterone/THDOC) are endogenous neuroactive steroids endowed with neuromodulatory actions in the central nervous system. Their best-characterized membrane-receptor-dependent action consists in the amplification of GABA-gated chloride currents mediated by specific interactions with the GABAA receptor complex, which appears responsible for the pharmacological effects (anxiolytic, anticonvulsant, hypn

Place of neurosteroids in the treatment of status epilepticus.

The treatment of refractory or super-refractory status epilepticus (SE) currently relies on low-evidence strategies, including general anesthetics to induce pharmacologic coma, ketogenic diet, immunosuppression, and other physical measures. Besides the formal uncertainty regarding efficacy, concerns have been about tolerability. In this situation, identification of alternative, higher evidence treatments is urgently needed. Allopregnanolone is an endogenous neurosteroid exerting a positive allosteric modulation on γ-aminobutyric acid (GABA)A receptors. In animal experiments it has been demonst

Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides.

The enzymatic pathways leading to the synthesis of bioactive steroids in the brain are now almost completely elucidated in various groups of vertebrates and, during the last decade, the neuronal mechanisms involved in the regulation of neurosteroid production have received increasing attention. This report reviews the current knowledge concerning the effects of neurotransmitters, peptide hormones, and neuropeptides on the biosynthesis of neurosteroids. Anatomical studies have been carried out to visualize the neurotransmitter- or neuropeptide-containing fibers contacting steroid-synthesizing n…

Role of neurosteroids in the anticonvulsant activity of midazolam.

BACKGROUND AND PURPOSE: Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA(A) receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA(A) receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. EXPERIMENTAL APPROACH: Mice were pretreated with neurosteroid synthesis inhibitors a…

Influence of neurosteroids on the pathogenesis of multiple sclerosis.

This paper summarizes neuroendocrine effects on myelination and their possible relevance for the pathogenesis of multiple sclerosis (MS). Steroid hormones known as neurosteroids are synthesized in the human central nervous system (CNS) and exert local effects on glial and neuronal tissue. Progesterone derivatives seem to act as promyelinating factors in the slow but continuous process of myelin maintenance in the adult human brain. Diminished production of these myelin-promoting factors may lead to the formation of structurally altered and less stable myelin, resulting in the observed patholog…

Neurosteroid treatment of postpartum depression and beyond.

Depression occurring during pregnancy or after delivery is one of the most common complications of childbirth and is associated with maternal morbidity and mortality. Here we review the breakthrough development of the first neuroactive steroid-based antidepressants approved for postpartum depression in the USA and their potential in other psychiatric illnesses.

Reinforcing effects of the neurosteroid allopregnanolone in rats.

The GABA(A) receptor positive modulator allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) is a potent neurosteroid with behavioral and biochemical characteristics similar to ethanol, barbiturates, and benzodiazepines. This suggests that neurosteroids may provide an alternative class of sedative/hypnotic, anticonvulsant, and anxiolytic pharmacotherapies. However, there is evidence from animal models that neurosteroids may be susceptible to abuse by humans. Thus, the present study evaluated the reinforcing effects of orally administered allopregnanolone in rats. In the first experiment, ma…

Нейростероиды, микробиота и нейроинфламмация: механистические понимания и терапевтические перспективы.

Ось кишечника (GBA) представляет собой сложную двунаправленную коммуникационную сеть, связывающую кишечник микробиота (GM) и центральную нервную систему (CNS). Недавние исследования показали, что нейростероиды (НН) играют важнейшую роль в модуляции нейроинфламмативной реакции и содействии нейрозащите. Тем временем, изменения ГМ связаны с различными нейро-воспалительными и нейродегенеративными условиями, такими, как множественный склероз, болезнь Альцгеймера и амиотропический боковой склероз. Цель этого обзора состоит в том, чтобы дать всеобъемлющий обзор сложных взаимосвязей между НС, ГМ и ней

Совпадение в аннотации оригинала
The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various…

Protective effects of corticosteroids and neurosteroids on cochlear injury.

Dysfunction of the cochlea causes sensorineural hearing loss. Glucocorticoids have been clinically applied for sensorineural hearing loss of … hlear injury, but there were limitations regarding glucocorticoid therapy. Recently, the actions of neurosteroids in the cochlea have drawn much attention from auditory researchers. Clinical and experimental studies of the auditory system have indicated that estrogens affect auditory perception. Furthermore, estrogens and dehydroepiandrosterone (DHEA) exhibit p …

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 relat…

Protocadherin 19 Clustering Epilepsy and Neurosteroids: Opportunities for Intervention.

Steroids yield great influence on neurological development through nuclear hormone receptor (NHR)-mediated gene regulation. We recently repo … oid-based therapeutics for CE. We review and assess the evidence for and against the implication of neurosteroids in the pathogenesis of CE and in view of their possible clinical benefit.

Brain edema in acute liver failure: role of neurosteroids.

Brain edema is a major neurological complication of acute liver failure (ALF) and swelling of astrocytes (cytotoxic brain edema) is the most … ty. Since increased neurosteroid biosynthesis has been reported to occur in brain in ALF, and since neurosteroids are known to protect against BBB breakdown, we examined whether neurosteroids exerted any protective effect on the slight permeability of the BBB after exposure to ammonia. We found that a nanomolar concentration (10nM) of the neurosteroids allopreg …

Ganaxolone in Epilepsy: Insights into a Neurosteroid-Based Therapy.

Neurological and neuropsychiatric disorders, particularly drug-resistant epilepsies and rare genetic syndromes such as CDKL5 deficiency disorder, pose significant therapeutic challenges. Ganaxolone (GNX), a synthetic neurosteroid and positive allosteric modulator of GABA-A receptors, has emerged as a promising treatment option due to its unique pharmacological properties. This review explores GNX's pharmacokinetic profile, preclinical evidence, and clinical applications. Preclinical studies have demonstrated its efficacy in reducing seizure frequency and severity across various epilepsy models

Glucocorticoid production in the thymus and brain: Immunosteroids and neurosteroids.

Glucocorticoids (GCs) regulate a myriad of physiological systems, such as the immune and nervous systems. Systemic GC levels in blood are of … vide useful insights, with a focus on local GC production in the thymus (immunosteroids) and brain (neurosteroids). Lastly, we suggest key areas for further research, such as the roles of immunosteroids and neurosteroids in neonatal programming and the potential clinical relevance of local GC modulators.