|Year : 2013 | Volume
| Issue : 2 | Page : 77-86
Biosynthesis, mechanism of action, and clinical mportance of neuroactive steroids: Pearls from literature
Pratishtha Vijaykumar Banga, Chetan Yuvraj Patil, Gaurav Anil Deshmukh, Kantilal Chainkaran Chandaliya, Mirza Shiraz Baig, Sudhakarrao Malhar Doifode
Department of Pharmacology, Government Medical College and Hospital, Aurangabad, Maharashtra, India
|Date of Submission||11-Feb-2012|
|Date of Acceptance||01-May-2012|
|Date of Web Publication||3-Jun-2013|
Mirza Shiraz Baig
Department of Pharmacology, Government Medical College and Hospital, Panchakki Road, Jubilee Park, Aurangabad - 431 001, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: To review the biosynthesis, mechanism, and important effects of neurosteroids on brain functions and brain disease by modulating synaptic and extrasynaptic transmission. Materials and Methods: This article is based on a comprehensive database search on the internet. Full-text articles in English, published between 2001 and 2012, were searched for, using the terms 'neuroactive steroids', 'neurotransmitter agents', 'molecular mechanism', 'depression', 'anxiety' 'neuropsychopharmacology', 'interactions with receptors', 'neuroprotection', and 'neuroendocrinology' to identify potential therapeutic targets. The reference lists of leading review articles identified during this search were checked for additional publications. Results: Neurosteroids regulate physiological functions of the central nervous system (CNS) and help in the neurodevelopmental functions relating to their neuroprotective effects in brain injury and possible therapeutic potential in brain lesions and other diseases of the nervous system. Neurosteroids have been shown to affect neuronal excitability via their interaction with the ligand-gated ion channel family, such as the GABA A and 5-HT 3 receptors, by acting genomically as well as nongenomically. By virtue of these properties, neurosteroids appear to be relevant to pathophysiology and pharmacological treatment of many psychiatric disorders, including not only the notable mood and anxiety disorders, but also psychotic disorders, childhood dementia and stress disorders. They have also been found to be involved in the pathophysiology and treatment of epilepsy, alcohol and substance abuse. Conclusion: Neurosteroids may become potential targets for pharmacological intervention in the future, with further research at the basic science level as well as in the context of large double-blinded placebo-controlled investigations to elicit their role fully in the understanding and management of various psychiatric conditions.
Keywords: Neuroactive steroids, neuropsychopharmacology, neurosteroids, psychoneuroendocrinology
|How to cite this article:|
Banga PV, Patil CY, Deshmukh GA, Chandaliya KC, Baig MS, Doifode SM. Biosynthesis, mechanism of action, and clinical mportance of neuroactive steroids: Pearls from literature. Int J Nutr Pharmacol Neurol Dis 2013;3:77-86
|How to cite this URL:|
Banga PV, Patil CY, Deshmukh GA, Chandaliya KC, Baig MS, Doifode SM. Biosynthesis, mechanism of action, and clinical mportance of neuroactive steroids: Pearls from literature. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2020 Jan 18];3:77-86. Available from: http://www.ijnpnd.com/text.asp?2013/3/2/77/112826
| Introduction|| |
Steroid hormones act by binding to their respective intracellular receptors. These receptors change their conformation subsequently by dissociation from chaperone molecules, for example, the heat shock proteins, and translocate to the nucleus where they bind as homo or heterodimers to the respective response elements that are located in the regulatory regions of target promoters.  Thus, steroid hormone receptors act as transcription factors in the regulation of gene expression. There is increasing evidence that certain steroids may alter neuronal excitability via the cell surface through interaction with certain neurotransmitter receptors. They are known as neurosteroids.
Genomic effects (limited by the rate of protein biosynthesis and requiring a time period from minutes to hours) and nongenomic effects (the modulatory effects requiring only milliseconds to seconds) of neurosteroids provide the molecular basis for a broad spectrum of steroid action on neuronal function and plasticity.  Neuroactive steroids can also act upon an array of neurotransmitter receptors and voltage-dependent ion channels, especially γ-aminobutyric acid (GABA), N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, glycine, serotonin, sigma-1, nicotinic and muscarinic acetylcholine receptors, as well as T-type Ca+2 channel, high voltage-activated Ca+2 channel, Na+ channel, Ca +2-activated K channel, and anion channels. 
Neuroactive steroids broadly refer to steroids that regulate the neuronal activities and physiological functions of the CNS. , They can be classified into two categories based on the source or production site: endogenous steroids and exogenous (synthetic) steroids. Endogenous steroids are subdivided into hormonal steroids (produced by the endocrine glands) and neurosteroids (produced by the nervous tissue) [Figure 1]. 
Neuroactive steroids have exhibited numerous important modulatory effects on brain functions and brain disease  by modulating almost all kinds of classical synaptic transmission, including glutamatergic, GABAergic, cholinergic, noradrenergic, dopaminergic, and serotonergic synaptic transmission, by altering the responsiveness of postsynaptic receptors or the presynaptic release of neurotransmitters.  Neuroactive steroids, under physiological conditions, can affect a spectrum of behavioral functions, such as sexual and feeding behavior, responses to stress, emotion, memory, and cognition.  Many studies have proven that they play important roles in the pathology and treatment of neurological and psychiatric disorders like epilepsy, premenstrual syndrome, schizophrenia, depression, anxiety, multiple sclerosis, and other neurodegenerative diseases. 
| Biosynthesis|| |
Endogenous neuroactive steroids are neuromodulators that can be synthesized de novo in the brain as well as in adrenal glands, ovaries, and testes. Among these compounds, the 3α,5α- and 3α, 5β-reduced metabolites of progesterone (3α,5α- and 3α,5β-tetrahydroprogesterone), deoxycorticosterone (3α,5α- and 3α,5β-tetrahydrodeoxycorticosterone), dehydroepiandrosterone (DHEA) (3α, 5α- and 3α,5β-androsterone), and testosterone (3α, 5α- and 3α,5β-androstanol) enhance GABAergic neurotransmission and produce inhibitory neurobehavioral effects such as anxiolytic, anticonvulsant, and sedative actions. The excitatory neuroactive steroids include the sulfated derivatives of pregnenolone and DHEA as well as the 3α,5α- and 3α,5β-reduced metabolites of cortisol. ,,
The biosynthetic pathway for these steroids is shown in [Figure 2]. The inhibitory neuroactive steroids with potent GABA A receptor-positive modulatory effects are highlighted in yellow, whereas the excitatory neuroactive steroids with weak GABA A receptor antagonist effects are highlighted in green. 
| Nomenclature|| |
The nomenclature of the steroids is provided in [Table 1]. 
|Table 1: International Union of Pure and Applied Chemistry: and conventional nomenclature|
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| Neurosteroids and Neurotransmitter Receptors|| |
Neurosteroids and γ-aminobutyric acid receptors γ-aminobutyric receptors
GABA receptors are pentameric heteromers and are members of the Cys-loop family of ligand-gated ion channels. This family also includes nicotinic acetylcholine receptors, ionotropic glycine receptors, serotonin 5-HT3 receptors, , and a recently described prokaryotic proton-gated channel.  GABA-gated conductance exerts an inhibitory influence mainly on the cell, though postsynaptic GABA response can be excitatory or inhibitory. There is a wide range of variations in GABA A receptors, depending upon structure of the subunit. Functional channels are formed from the assembly of 2α subunits (from α1, α2, α3, α4, α5, α6), 2β subunits (from β1, β2, β3), plus one additional subunit, often a γ subunit (from γ1, γ2, γ3), but sometimes from a δ, ε, π, or θ subunit.  The α1β2γ2 subunit combination is estimated to be the most widespread combination in the mammalian brain.  Moreover, the γ2 subunit contains sequence motifs responsible for synaptic targeting; so this subunit appears particularly important for synaptic localization/clustering of GABA A receptors
A schematic of a single GABA A receptor subunit is shown in [Figure 3]a.  The pentameric receptor with sites of action for important modulatory drugs is shown in [Figure 3]b. 
|Figure 3: Schematic and putative binding sites of γ-aminobutyric acid receptor. (a) A single subunit of the γ-aminobutyric acid receptor, highlighting topology. M1– M4 represent transmembrane domains. The M2 transmembrane domain (gray) forms an important part of the chloride channel pore. (b) Pentameric structure of a typical γ-aminobutyric acid receptor. Several putative sites of γ-aminobutyric acid and modulatory drugs, including neurosteroids, are shown. The indication that steroids act on the γ-aminobutyric acid receptor from within the transmembrane domains is supported by pharmacological studies and by recent site-directed mutagenesis studies.|
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Interaction of neurosteroids with γ-aminobutyric acid receptors
The 3α-reduced metabolites of progesterone and deoxycorticosterone, 3α,5α-tetrahydroprogesterone (3α,5α-THP; 3α-hydroxy-5α-pregnan-20-one; allopregnanolone) and 3α, 5α-tetrahydrodeoxycorticosterone (3α,5α-THDOC; 3α,21-dihydroxy-5α-pregnan-20-one; allotetrahydrodeoxycorticosterone), were the first steroids that have been shown to modulate neuronal excitability via their interaction with GABA type A receptors. ,
Qualitatively, interactions of neurosteroids with GABA A receptors can be potentiating actions or antagonistic actions. Of these two, the most prominent potentiating action is seen with the endogenous 3α, 5α-THP (3α5αP or allopregnanolone), 3α,5β-THP (3α5βP or pregnanolone), (3α,5α)-3,21-dihydroxypregnan-20-one (3α5α-THDOC), and (3α, 5β)-3, 21-dihydroxypregnan-20-one (3α5β-THDOC). ,,, This potent positive allosteric modulatory action on GABA A receptors is because they enhance the GABA-evoked chloride current through an increase in the frequency and/or duration of openings of the GABA-gated chloride channel. ,, These steroids are synthesized from cholesterol via progesterone or deoxycorticosterone; therefore, fluctuations in the levels of progesterone may influence the modulatory effects that neurosteroids have over the function of the GABA A receptors. ,
Steroids sulfated at C3, typified by pregnenolone sulfate (PS) and sulfated pregnane steroids, with either α or β stereochemistry at C3 and at C5, have noncompetitive antagonist action. , The IC 50 (half maximal inhibitory concentration) for the action of this class of neuroactive steroids varies with the activation state of the receptor, but typical values are in the high nanomolar to micromolar range. Finally, 3β-OH steroids can also antagonize GABA A receptors in a manner similar to C3 sulfated steroids, but the potency, and perhaps efficacy, of 3β-OH steroids is weaker than that of sulfated steroids. 
Recent results have shown evidence of neurosteroid action on two sites of GABA A receptors. One site spans the M1 and M4 transmembrane domains of the α-subunit and accounts for the potentiating actions of some steroids. Another site, between the M1 transmembrane domain of the α-subunit and the M3 domain of the β-subunit, is responsible for direct gating of the channel by steroids. These sites are schematized in [Figure 4]. 
|Figure 4: Top-down view of the pentameric γ-aminobutyric acid receptor showing proposed sites of potentiation and direct gating for neurosteroids.|
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Direct gating by steroids is inefficient, with maximum responses well below the responses generated by saturating GABA. Nevertheless, even small currents resulting from direct gating can have a significant impact on cellular excitability. Furthermore, studies done recently have reported that the kinetics of onset and offset of direct gating are particularly slow.  This likely has led to an underappreciation of the potency with which neurosteroids directly activate the channel.
Neuroactive steroids are among the most potent and efficacious modulators of GABA A receptors and their potency is less than that of benzodiazepines (half-maximum effects in the nanomolar concentration range), but benzodiazepines typically generate less than threefold maximum potentiation of GABA responses, and therefore are of lower efficacy. The efficacy of neuroactive steroids, which can approach 10- to 20-fold maximum potentiation at low GABA concentration, rivals barbiturate potentiation, but the steroids are much more potent.  There are many review articles in the literature sho wing that the action of neurosteroids is highly specific, being both brain region and neuron dependent. The mechanisms of this selectivity involve the composition of the GABA A receptor subunit, the differential expression of steroid-synthesizing and -metabolizing enzymes, and local steroid metabolism and phosphorylation mechanisms. ,
Neuroactive steroids act on both synaptic and extrasynaptic GABA A receptors. Moreover, extrasynaptic GABA A receptors are highly sensitive to neurosteroids  and appear to play a vital role in the neuronal plasticity changes that accompany stress, puberty, and the ovarian cycle. ,
Neurosteroids and expression of the γ-aminobutyric acid receptors
Previously, it was assumed that the neuroactive steroids modulating GABA A receptors do not regulate gene expression via intracellular steroid receptors because they do not bind to a known steroid hormone receptor. Research done using a cotransfection system with recombinant progesterone receptors and the mouse mammary tumor virus (MTV) has shown that the neuroactive steroids like 3α,5α-THP and 3α, 5α-THDOC activate gene expression effectively and enhance the nuclear translocation. 
Recently, it has been shown that on chronic exposure to neuroactive steroids such as 3α,5α-THP and 3α,5α-THDOC, both chronic exposure and withdrawal from exogenous neurosteroids increase expression of the GABA A receptor α4-subunit to produce CNS hyperexcitability.  This increase in the expression of the α4-subunit is responsible for benzodiazepine insensitivity, one common factor in rodent models and the clinical presentation of premenstrual dysphoric disorder.
Neurosteroids and various other neurosteroid receptors
Because of the high molecular complexity of the GABA A receptors, studies have been done using the 5-HT 3 receptor for a further characterization of the modulation of ligand-gated ion channels by steroids.  In contrast to GABA A receptors, 5-HT 3 receptors are functional as homomers (5-HT 3 type A receptors). However, recently a second subunit, the B form of the 5-HT 3 receptor, has been identified. Though the subunit composition of the 5-HT 3 receptor is far less complex than that of GABA A receptors, the 5-HT 3 receptor, like GABA receptors, belongs to the family of ligand-gated ion channels with four transmembrane-spanning domains. 
Gonadal steroids such as 17β-estradiol and progesterone may also act as functional antagonists at the 5-HT 3 receptor, as shown in the study using whole-cell voltage clamp recordings of HEK 293 cells expressing the 5-HT 3 type A receptor stably.  This antagonistic property of gonadal steroids at the 5-HT 3 receptor may play a role in the development and course of nausea during pregnancy and of psychiatric disorders such as postpartum psychosis. Functional antagonistic properties at this 5-HT 3 receptor could also be shown for allopregnanolone, 17-ethinyl-17-estradiol, 17 estradiol, mestranol, testosterone, and R 5020, but not for PS and cholesterol.  This explains the dependency of modulation of the function of the 5-HT 3 receptors by steroids on their respective molecular structures.
Members within the ligand-gated ion channel family, other than GABA A and 5-HT 3 , like nicotinic acetycholine receptors, glycine receptors, and also within the glutamate receptor family, NMDA receptors, AMPA receptors, and kainate receptors have been shown to be steroid sensitive and targets for steroid modulation.  The oxytocin receptor and σ-receptors were identified as sensitive to steroid modulation, and σ-receptors have less clear evidence because detailed molecular characterization is still unavailable. , Neurotransmitter receptors and their interaction with neurosteroids along with type of modulation are provided in [Table 2]. 
| Neurosteroids and Development and Repair of the CNS Following Injury|| |
It is a well-known fact that neurosteroids regulate the physiological functions of the CNS, which also helps in the neurodevelopmental functions. In animal models, neurosteroids have been shown to have organizational effects on synaptic connectivity and neuronal differentiation in limbic and hypothalamic areas controlling reproductive behaviors and the release of pituitary hormones. Organizational effects have also been seen in other brain regions such as the cerebellum, cerebral cortex, and the hippocampal formation. In addition, neuroactive steroids regulate the development of glial cells.  Indeed, morphology, immunoreactivity, enzymatic activity, and gene expression of the astroglia are sexually dimorphic in several brain areas and can be modified by postnatal actions of neuroactive steroids.
In humans, absent or reduced concentrations of neurosteroids both during development and in adult life may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination,  increased memory, and reduced neurotoxicity.
Progesterone and its metabolites also promote the viability of neurons in the adult brain and spinal cord. Studies have been conducted to review their neuroprotective effects in traumatic brain injury, experimentally induced ischemia, spinal cord lesions, and a genetic model of motor neuron disease. Progesterone plays an important role in developmental myelination and in myelin repair,  and the aging nervous system appears to remain sensitive to some of the beneficial effects of progesterone. This denotes that neurosteroids have possible therapeutic potential for the treatment of brain lesions and other diseases of the nervous system.
| Clinical Importance of Neruoactive Steroids|| |
Role in mood disorders
Depression is the second most common chronic condition in clinical practice and will become the second leading cause of death or disability worldwide by the year 2020. Approximately two-thirds of the anxious or depressed patients respond to the currently available treatments but the magnitude of improvement is still disappointing.  Numerous observations appear to confirm the involvement of neurosteroids in depression, with respect to both empirical findings as well as antidepressive treatment modalities. It has been proposed that in depressive conditions (including premenstrual dysphoric disorders), neurosteroid effects are mediated by the modulation of noradrenergic, serotonergic, and anti-glucocorticoid systems.  Moreover, antidepressants appear to influence neurosteroidogenesis, affecting enzyme activity and the hypothalamo-pituitary-adrenal (HPA) axis.
Pregnenolone, the main precursor for the synthesis of neuroactive steroids, and its sulfated derivate, PS, may directly modulate neurotransmitter receptors, and thereby modulate depressive behavior. Preclinical studies had shown an antidepressant-like profile of pregnenolone/PS in the forced swimming procedure,  probably through the interaction with the σ1 receptor.  Like PS, dehydroepiandrosterone sulfate (DHEAS) also has been shown to exert antidepressant-like effects in the forced swimming procedure, mediating throughout the interaction with the σ1 receptor.
In humans, studies focused on DHEA/DHEAS plasma levels as logical markers of depression revealed inconsistent results. In patients suffering from depression, decreased DHEAS plasma levels and DHEA salivary concentrations have been observed. In contrast, other studies reported significant elevations of DHEAS 24-hour urinary levels and diurnal minimal and mean DHEA plasma concentrations. ,, The clinical studies have demonstrated that the levels of 3α,5α-THP and 3α,5β-THP in the cerebrospinal fluid (CSF) of patients with unipolar major depression were significantly lower as compared to those in normal controls. ,
In major depression, studies investigating the therapeutic effects of DHEA revealed promising results, whereas results are lacking for progesterone. Administration of fluoxetine has been shown to increase 3α,5α-THP and 3α,5β-THP plasma and CSF levels and to decrease 3β,5α-THP concentrations concomitantly in patients suffering from depression. ,, However, in contrast to preclinical data, treatment with tricyclic antidepressants influenced 3α,5α-THP, 3α,5β-THP, and 3β,5α-THP levels in a similar way for selective serotonin reuptake inhibitors (SSRIs). 
Treatment with DHEA either as the only medication or as an adjunct to stable antidepressant medication may exert beneficial effects on depressed mood. Therefore, the role of DHEA in depression and antidepressant therapy requires further consideration in the future.
Role in anxiety and response to stress
Animal studies have shown that positive modulation of the GABA A receptor results in anxiolytic activity, , whereas negative modulation of this receptor produces anxiogenic activity.  Preclinical studies suggested an anxiogenic effect of pregnenolone in the elevated plus maze test in mice and of a biphasic response curve of PS being anxiogenic at higher and anxiolytic at lower doses.
In humans, lowered PS levels have been detected in patients suffering from generalized anxiety disorder and generalized social phobia and have been suggested to represent a compensatory mechanism. [14.15] In line with a biphasic response curve at GABA A receptors, DHEA/DHEAS showed anxiolytic activity in the plus maze test at lower concentrations, whereas in vivo studies suggested a GABA A receptor-antagonistic profile of DHEAS. In addition, DHEA/DHEAS elevations have been found in post-traumatic stress disorder (PTSD),  which have recently been related to suicide attempts of veterans suffering from PTSD.
Anxiolytic effects of progesterone have been demonstrated in several preclinical trials, but anxiolytic properties of exogenously administered progesterone are not mediated by a direct interaction with progesterone receptors but rather by their in vivo conversion to 3α,5α-THP. , Furthermore, recently, functional imaging studies suggested that progesterone, via its conversion to 3α,5α-THP, may influence states of human anxiety by modulating amygdala activity.  Naturally occurring 3α-reduced neuroactive steroids might be involved in the regulation of the endogenous stress response. Mild stress conditions are followed by increases in 3α,5β-THP and 3α,5α-THDOC. These neuroactive steroids, in turn, decrease the stress-induced corticosterone release. 
Patients of panic disorder and agarophobia have shown elevated plasma concentrations of 3α-reduced neuroactive steroids  compared with healthy controls, whereas the concentrations of 3α,5α-THP, an antagonistic stereoisomer of 3β,5α-THP, were decreased. , This was supported by an experimental panic induction model for the pathophysiology of panic disorder. 
The first evidence that the levels of neuroactive steroids in the brain are affected by acute stress was provided by the observation that forced swimming induced rapid increases in the concentrations of progesterone and its metabolites 3α,5α-THP and 3α,5α-THDOC in the cerebral cortex, hypothalamus, and plasma of rats. , Among the neurotransmitters, GABA plays a central role and contributes to the rapid coordination of behavioral, emotional, neuroendocrine, and metabolic aspects of the response to acute stress. Further, it was supported by the observations that various acute stress paradigms, including mild foot shock, inhalation of carbon monoxide, forced swimming, and exposure to a new environment, all of which also elicit anxiety-related behavior, induced a rapid and reversible downregulation of GABAergic transmission. Importance of these observed changes in biochemical parameters of GABAergic transmission elicited by stress was provided by the finding that receptor function or negative allosteric modulators of the GABA A receptor complex (anxiogenic β-carbolines) mimicked the effects of acute stress. 
Role in psychotic disorders
The role of stress in the development and exacerbation of psychosis in schizophrenia has been demonstrated. Abnormal dopaminergic activity has been well documented in schizophrenia. There is enough evidence showing a defi cit of GABAergic and glutamatergic activity in Neuroactive steroids, as we know, modulate the activity of all of these systems, both directly and indirectly, therefore contributing to the pathophysiology of the illness. Hence, they may play a role in the therapeutic benefi ts of antipsychotic drugs, particularly those whose actions involve the GABA A receptor complex.
Studies have reported low DHEA levels in the morning in chronically ill unmedicated patients with schizophrenia, compared with healthy control subjects. However, a recent study reported elevated DHEA plasma levels and, interestingly, DHEA levels correlated inversely with the severity of negative symptoms in drug-free men with first-episode psychosis. , There have also been reports of elevated plasma DHEAS levels in medicated young men with psychosis, as well as of low estradiol and high testosterone but unchanged DHEAS plasma levels in medicated young women with psychosis, when compared with healthy control subjects.  Studies have found cortisol levels to be directly and testosterone levels to be inversely correlated with the severity of negative symptoms in patients with schizophrenia. It was further supported by studies involving measurement of cortisol-to-DHEA and cortisol-to-DHEAS ratios in patients with schizophrenia, which were significantly higher than those in healthy control subjects, although the ratios did not correlate with the severity of symptoms of schizophrenia. ,
Abnormal serum levels of progesterone have also been reported in some patients with schizophrenia.  It may be possible that progesterone acts like an endogenous antipsychotic and anxiolytic and that an increase in progesterone levels during the early phase of the illness and during times of stress serves to restore normal functioning. Steroid levels in patients with schizophrenia, compared with control subjects are shown in [Table 3]. 
|Table 3: Steroid levels in patients with schizophrenia, compared with control subjects|
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To our surprise, it has been found that concentrations of neuroactive steroids may be affected by antipsychotic treatment. Atypical, but not typical, antipsychotics have been found to alter brain levels of neurosteroids. , The atypical agents like olanzapine and clozapine increase concentrations of cortical 3α,5α-THP and progesterone dose dependently, and clozapine increases concentrations of cortical 3α,5α-THDOC following acute administration in rats.  Antipsychotic-induced alterations in neurosteroid levels may contribute to the antipsychotic effects of these drugs.
DHEA: Dehydroepiandrosterone; DHEAS: Dehydroepiandrosterone sulfate; PROG: Progesterone Reduced GABAergic neurotransmission may contribute to the pathophysiology of schizophrenia. Thus, antipsychotic-induced increase of 3α,5α-THP, a positive allosteric modulator of GABA A receptors, and decrease of DHEA and DHEAS, negative allosteric modulators of GABA A receptors, may augment GABAergic tone in the cortex, resulting in improvement in symptoms. 
Role in childhood disorders
During the past few decades, there has been a significant rise in the incidence rates of childhood behavioral disorders appearing on the horizon; among these disorders are: Attention deficit/hyperactivity disorder (ADHD), autistic spectrum disorder, and the like.  Neurosteroids have also been found to play a role in some childhood disorders. Studies have found low plasma levels of DHEA and pregnenolone in children with ADHD and inverse correlations between clinical symptomatology of ADHD and plasma levels of DHEA and pregnenolone.  In addition, plasma levels of DHEA and DHEAS were inversely correlated with hyperactivity, suggesting a possible protective effect on the expression of ADHD symptomatology.  Moreover, a significant increase in serum levels of DHEA and DHEAS was associated with a successful treatment of three months with methylphenidate.  Others have reported significantly higher levels of DHEAS and allopregnanolone in conduct disorder, with the DHEAS levels positively correlated with the intensity of aggression and delinquency.
Role in alcohol and substance abuse
A wide body of experimental evidence accumulated over the past two decades suggests that the GABA A receptor is an important and sensitive neurochemical target in the acute and chronic actions of ethanol. As we know, GABA A receptors are targets for several classes of clinically relevant drugs, including benzodiazepines, barbiturates, and general anesthetics, as well as for endogenous compounds such as neuroactive steroids, all of which modulate receptor function allosterically.
Recent studies have suggested that many of the acute pharmacological actions of ethanol are mediated by an increase in the brain levels of neuroactive steroids. Acute systemic administration of ethanol in rats was thus found to result in marked increases in the concentrations of 3α,5α-THP in plasma, cerebral cortex, and hippocampus.  A stimulatory effect of ethanol on the HPA axis is thought to represent the main mechanism by which this drug increases 3α,5α-THP levels. The possibility that the increase in the concentration of 3α,5α-THP in isolated hippocampal tissue induced by ethanol as well as by progesterone might result in the modulation of GABA A receptors, which are sensitive targets of neuroactive steroids, was subsequently tested and proved. 
Chronic administration and subsequent withdrawal of ethanol elicits neurochemical and molecular effects in rat brain, that is, changes in the properties of the receptor accompanied by changes in the abundance of specific receptor subunit,  which are similar to those induced by drugs that potentiate the function of the GABA A receptors. Indeed, altered function of GABA A receptors, characterized by a decreased responsiveness to GABA A , decreased sensitivity to ethanol, cross-tolerance to benzodiazepines and barbiturates, as well as increased sensitivity to neuroactive steroids and inverse agonists is thought to be important in the development of overall tolerance to and dependence on ethanol.  Although the molecular mechanisms remain unclear for this action, it has been proposed that they include changes in receptor density and in post-translational modification of protein.
Treatment with ﬂuoxetine results in an earlier rise in concentrations of 3α,5α-THP and is accompanied by a decrease in depression and anxiety during ethanol withdrawal. Thus, SSRIs may be recommended as a treatment option during uncomplicated ethanol withdrawal in that they increase the concentrations of 3α-reduced neuroactive steroids. 
Role in dementia and memory disorders
Sulfate derivatives of pregnanolone have been shown to exert their neuroprotective effects via inhibition of the function of NMDA receptors. Anti-glucocorticoid effects of DHEA have been reported in vivo, in addition to the effects of DHEA via the cell membrane. Therefore, such steroids might possess nootropic properties.
Animal studies have shown DHEA to enhance memory retention in mice; also, prolonged intracerebroventricular infusion of PS enhanced cognitive performance in mice.  Alzheimer's disease is a progressive neurological disease of the brain and is the most common form of dementia; it affects an estimated 10 million people worldwide.  There is evidence that levels of DHEA decrease with age and decreased concentrations of DHEA have been reported in patients suffering from Alzheimer's disease and multi-infarct dementia.  Decreased concentrations of DHEAS may constitute an enhanced risk for the development of Alzheimer's disease. Moreover, a reduced DHEA/cortisol ratio has been found in Alzheimer s disease that becomes even more prominent upon challenge of the HPA system with the corticotrophin-releasing hormone (CRH).  Systematic research as to whether DHEA supplementation may enhance cognitive performance in normal aging people or in dementia disorders is scarcely available.
Role in epilepsy
Drugs like benzodiazepines and barbiturates that enhance the function of GABA A receptors as well as drugs targeting the GABA-binding site of the GABA A receptor are commonly used as effective antiepileptic agents. 3α-reduced neuroactive steroids, therefore, should also possess anticonvulsant activity, which was proved in various animal models.  Progesterone as a precursor molecule has been reported to decrease epileptiform discharges in women suffering from catamenial epilepsy. Nevertheless, 3α-reduced neuroactive steroids may constitute a promising new treatment option for distinct forms of epilepsy.  Ganaxolone (GNX) is a novel neuroactive steroid, which modulates the GABA A receptor complex via a unique recognition site, different from those of benzodiazepines and barbiturates. ,, Preclinical data is now available to demonstrate that GNX possesses broad-spectrum anticonvulsant activity with potential clinical utility in both generalized and partial seizure, as well as cocaine-induced seizures. Moreover, safety and efficacy trial of GNX in the pediatric population with refractory infantile spasms recorded at least 50% reduction in spasm frequency in 33% of these subjects. However, further investigation with a randomized, controlled study design is required before this agent can be recommended for clinical use. 
| Conclusion|| |
Awareness of the prominent role of neurosteroids in neuropsychiatric disorders is rapidly increasing. Additional factors regarding their central role in normal physiological functioning as well as in illness continue to be detailed in numerous basic and clinical investigations over the past few years. Moreover, at this stage in neurosteroid research, which pertains to human epidemiological and treatment trials of mental illness, much controversial data exist in the literature. Many findings, for example, that have been noted in animal studies have yet to be replicated in humans. Finally, although preliminary investigation into the use of neurosteroid analogs or manipulation of the neurosteroid system in treatment remains promising, such as the use of ganaxolone in epilepsy, research of such nature is in its early stages and no firm clinical applications exist at present. Further research at the basic science level as well as in the context of large double-blinded placebo-controlled investigations is mandated to fully elicit the role of neurosteroids in the understanding and management of various psychiatric conditions.
| References|| |
|1.||Rupprecht R. Neuroactive steroids: Mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003;28:139-68. |
|2.||Zheng P. Neuroactive steroid regulation of neurotransmitter release in the CNS: Action, mechanism and possible significance. Prog Neurobiol 2009;89:134-52. |
|3.||Melcangi RC, Panzica G, Garcia-Segura LM. Neuroactive steroids: Focus on human brain. Neuroscience 2011;191:1-5. |
|4.||Morrow AL. Recent developments in the significance and therapeutic relevance of neuroactive steroids--Introduction to the special issue. Pharmacol Ther 2007;116:1-6. |
|5.||Rupprecht R, di Michele F, Hermann B, Ströhle A, Lancel M, Romeo E, et al. Neuroactive steroids: Molecular mechanisms of action and implications for neuropsychopharmacology. Brain Res Brain Res Rev 2001;37:59-67. |
|6.||Akk G, Covey DF, Evers AS, Steinbach JH, Zorumski CF, Mennerick S. Mechanisms of neurosteroid interactions with GABA(A) receptors. Pharmacol Ther 2007;116:35-57. |
|7.||Mellon SH, Griffin LD. Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab 2002;13:35-43. |
|8.||Herd MB, Belelli D, Lambert JJ. Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. Pharmacol Ther 2007;116:20-34. |
|9.||Prajapati R, Umbarkar R, Parmar S, Sheth N. Antidepressant like activity of Lagenaria siceraria (Molina) Standley fruits by evaluation of the forced swim behavior in rats. Int J Nutr Pharmacol Neurol Dis 2011;1:152-6 |
|10.||Strous RD, Maayan R, Weizman A. The relevance of neurosteroids to clinical psychiatry: From the laboratory to the bedside. Eur Neuropsychopharmacol 2006;16:155-69. |
|11.||Uzunova V, Sampson L, Uzunov DP. Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action. Psychopharmacology 2006;186:351-61. |
|12.||Eser D, Schüle C, Baghai TC, Romeo E, Rupprecht R. Neuroactive steroids in depression and anxiety disorders: Clinical studies. Neuroendocrinology 2006;84:244-54. |
|13.||MacKenzie EM, Odontiadis J, Le Mellédo JM, Prior TI, Baker GB. The relevance of neuroactive steroids in schizophrenia, depression, and anxiety disorders. Cell Mol Neurobiol 2007;27:541-74. |
|14.||Eser D, Schüle C, Baghai TC, Romeo E, Uzunov DP, Rupprecht R. Neuroactive steroids and affective disorders. Pharmacol Biochem Behav 2006;84:656-66. |
|15.||Eser D, Baghai TC, Schüle C, Nothdurfter C, Rupprecht R. Neuroactive steroids as endogenous modulators of anxiety. Curr Pharm Des 2008;14:3525-33. |
|16.||Biggio G, Concas A, Follesa P, Sanna E, Serra M. Stress, ethanol, and neuroactive steroids. Pharmacol Ther 2007;116:140-71. |
|17.||Reddy DS. Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions. Neuroscience 2006;138:911-20. |
|18.||Shulman Y, Tibbo PG. Neuroactive steroids in schizophrenia. Can J Psychiatry 2005;50:695-702. |
|19.||Ritsner MS, Strous RD. Neurocognitive deficits in schizophrenia are associated with alterations in blood levels of neurosteroids: A multiple regression analysis of findings from a double-blind, randomized, placebo-controlled, crossover trial with DHEA. J Psychiatr Res 2010;44:75-80. |
|20.||Al-Sharbati M. The emergence of behavioral disorders in children and adolescents. Int J Nutr Pharmacol Neurol Dis 2012;2:1-2. |
|21.||Singhal AK, Naithani V, Bangar OP. Medicinal plants with a potential to treat Alzheimer and associated symptoms. Int J Nutr Pharmacol Neurol Dis 2012;2:84-91. |
|22.||Ramachandrannair R. Steroids in childhood epilepsy. Ann Indian Acad Neurol 2006;9:199-206. |
|23.||Reddy DS. Pharmacotherapy of catamenial epilepsy. Indian J Pharmacol 2005;37:288-93. |
|24.||Anovadiya AP, Sanmukhani JJ, Tripathi CB. Epilepsy: Novel therapeutic targets. J Pharmacol Pharmacother 2012;3:112-7. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]
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|[Pubmed] | [DOI]|