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Doodipala Samba Reddy - One of the best experts on this subject based on the ideXlab platform.
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neurosteroid structure activity relationships for functional activation of extrasynaptic δgaba a receptors
Journal of Pharmacology and Experimental Therapeutics, 2016Co-Authors: Chase M Carver, Doodipala Samba ReddyAbstract:Synaptic GABAA receptors are primary mediators of rapid inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurologic disorders. The δ-subunit GABAA receptors are expressed extrasynaptically in the dentate gyrus and contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. However, the neurosteroid structure-function relationship at δGABA(A) receptors within the native hippocampus neurons remains unclear. Here we report a structure-activity relationship for neurosteroid modulation of extrasynaptic GABAA receptor-mediated tonic inhibition in the murine dentate gyrus granule cells. We recorded neurosteroid allosteric potentiation of GABA as well as direct activation of tonic currents using a wide array of natural and synthetic Neurosteroids. Our results shows that, for all Neurosteroids, the C3α-OH group remains obligatory for extrasynaptic receptor functional activity, as C3β-OH epimers were inactive in activating tonic currents. Allopregnanolone and related pregnane analogs exhibited the highest potency and maximal efficacy in promoting tonic currents. Alterations at the C17 or C20 region of the neurosteroid molecule drastically altered the transduction kinetics of tonic current activation. The androstane analogs had the weakest modulatory response among the analogs tested. Neurosteroid potentiation of tonic currents was completely (approximately 95%) diminished in granule cells from δ-knockout mice, suggesting that δ-subunit receptors are essential for neurosteroid activity. The neurosteroid sensitivity of δGABA(A) receptors was confirmed at the systems level using a 6-Hz seizure test. A consensus neurosteroid pharmacophore model at extrasynaptic δGABA(A) receptors is proposed based on a structure-activity relationship for activation of tonic current and seizure protection.
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perimenstrual like hormonal regulation of extrasynaptic δ containing gabaa receptors mediating tonic inhibition and neurosteroid sensitivity
The Journal of Neuroscience, 2014Co-Authors: Chase M Carver, Omkaram Gangisetty, Doodipala Samba ReddyAbstract:Neurosteroids are endogenous regulators of neuronal excitability and seizure susceptibility. Neurosteroids, such as allopregnanolone (AP; 3α-hydroxy-5α-pregnan-20-one), exhibit enhanced anticonvulsant activity in perimenstrual catamenial epilepsy, a neuroendocrine condition in which seizures are clustered around the menstrual period associated with neurosteroid withdrawal (NSW). However, the molecular mechanisms underlying such enhanced neurosteroid sensitivity remain unclear. Neurosteroids are allosteric modulators of both synaptic (αβγ2-containing) and extrasynaptic (αβδ-containing) GABAA receptors, but they display greater sensitivity toward δ-subunit receptors in dentate gyrus granule cells (DGGCs). Here we report a novel plasticity of extrasynaptic δ-containing GABAA receptors in the dentate gyrus in a mouse perimenstrual-like model of NSW. In molecular and immunofluorescence studies, a significant increase occurred in δ subunits, but not α1, α2, β2, and γ2 subunits, in the dentate gyrus of NSW mice. Electrophysiological studies confirmed enhanced sensitivity to AP potentiation of GABA-gated currents in DGGCs, but not in CA1 pyramidal cells, in NSW animals. AP produced a greater potentiation of tonic currents in DGGCs of NSW animals, and such enhanced AP sensitivity was not evident in δ-subunit knock-out mice subjected to a similar withdrawal paradigm. In behavioral studies, mice undergoing NSW exhibited enhanced seizure susceptibility to hippocampus kindling. AP has enhanced anticonvulsant effects in fully kindled wild-type mice, but not δ-subunit knock-out mice, undergoing NSW-induced seizures, confirming δ-linked neurosteroid sensitivity. These results indicate that perimenstrual NSW is associated with striking upregulation of extrasynaptic, δ-containing GABAA receptors that mediate tonic inhibition and neurosteroid sensitivity in the dentate gyrus. These findings may represent a molecular rationale for neurosteroid therapy of catamenial epilepsy.
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a mouse kindling model of perimenstrual catamenial epilepsy
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Doodipala Samba Reddy, Jordan Gould, Omkaram GangisettyAbstract:Catamenial epilepsy is caused by fluctuations in progesterone-derived GABAA receptor-modulating anticonvulsant Neurosteroids, such as allopregnanolone, that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy by using the neurosteroid-withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (midluteal phase) and increases during their withdrawal (perimenstrual periods) in close association with GABAA receptor plasticity. A chronic seizure condition was created by using the hippocampus kindling model in female mice. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Elevated neurosteroid exposure reduced seizure expression in fully kindled mice. Fully kindled mice subjected to neurosteroid withdrawal showed increased generalized seizure frequency and intensity and enhanced seizure susceptibility. They also showed reduced benzodiazepine sensitivity and enhanced neurosteroid potency, similar to the clinical catamenial seizure phenotype. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the α4 and δ subunits of GABAA receptors in the hippocampus. These findings demonstrate that endogenous Neurosteroids protect against seizure susceptibility and their withdrawal, such as that which occurs during menstruation, leads to exacerbation of seizure activity. This is possibly caused by specific changes in GABAA receptor-subunit plasticity and function, therefore providing a novel mouse model of human perimenstrual catamenial epilepsy that can be used for the investigation of disease mechanisms and new therapeutic approaches.
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neurosteroid withdrawal regulates gaba a receptor α4 subunit expression and seizure susceptibility by activation of progesterone receptor independent early growth response factor 3 pathway
Neuroscience, 2010Co-Authors: Omkaram Gangisetty, Doodipala Samba ReddyAbstract:Neurosteroids regulate GABA-A receptor plasticity. Neurosteroid withdrawal occurs during menstruation and is associated with a marked increase in expression of GABA-A receptor α4-subunit, a key subunit linked to enhanced neuronal excitability, seizure susceptibility and benzodiazepine resistance. However, the molecular mechanisms underlying the upregulation of α4-subunit expression remain unclear. Here we utilized the progesterone receptor (PR) knockout mouse to investigate molecular pathways of PR and the transcription factor early growth response factor-3 (Egr3) in regulation of the GABA-A receptor α4-subunit expression in the hippocampus in a mouse neurosteroid withdrawal paradigm. Neurosteroid withdrawal induced a threefold increase in α4-subunit expression in wild-type mice, but this upregulation was unchanged in PR knockout mice. The expression of Egr3, which controls α4-subunit transcription, was increased significantly following neurosteroid withdrawal in wild-type and PR knockout mice. Neurosteroid withdrawal-induced α4-subunit upregulation was completely suppressed by antisense Egr3 inhibition. In the hippocampus kindling model of epilepsy, there was heightened seizure activity, significant reduction in the antiseizure sensitivity of diazepam (a benzodiazepine insensitive at α4βγ-receptors) and conferral of increased seizure protection of flumazenil (a low-affinity agonist at α4βγ-receptors) in neurosteroid-withdrawn wild-type and PR knockout mice. These observations are consistent with enhanced α4-containing receptor abundance in vivo. Neurosteroid withdrawal-induced seizure exacerbation, diazepam insensitivity, and flumazenil efficacy in the kindling model were reversed by inhibition of Egr3. These results indicate that neurosteroid withdrawal-induced upregulation of GABA-A receptor α4-subunit expression is mediated by the Egr3 via a PR-independent signaling pathway. These findings help advance our understanding of the molecular basis of catamenial epilepsy, a neuroendocrine condition that occurs around the perimenstrual period and is characterized by neurosteroid withdrawal-linked seizure exacerbations in women with epilepsy.
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Neurosteroid Replacement Therapy for Catamenial Epilepsy
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2009Co-Authors: Doodipala Samba ReddyAbstract:Perimenstrual catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age with drug-refractory epilepsy. Enhanced seizure susceptibility in perimenstrual catamenial epilepsy is believed to be due to the withdrawal of the progesterone-derived GABAA receptor modulating neurosteroid allopregnanolone as a result of the fall in progesterone at the time of menstruation. Studies in a rat pseudopregnancy model of catamenial epilepsy indicate that after neurosteroid withdrawal there is enhanced susceptibility to chemoconvulsant seizures. There is also a transitory increase in the frequency of spontaneous seizures in epileptic rats that had experienced pilocarpine-induced status epilepticus. In the catamenial epilepsy model, there is a marked reduction in the antiseizure potency of anticonvulsant drugs, including benzodiazepines and valproate, but an increase in the anticonvulsant potency and protective index of Neurosteroids such as allopregnanolone and the neurosteroid analog ganaxolone. The enhanced seizure susceptibility and benzodiazepine-resistance subsequent to neurosteroid withdrawal may be related to reduced expression and altered kinetics of synaptic GABAA receptors and increased expression of GABAA receptor subunits (such as α4) that confer benzodiazepine insensitivity. The enhanced potency of Neurosteroids may be due to a relative increase after neurosteroid withdrawal in the expression of neurosteroid-sensitive δ-subunit-containing perisynaptic or extrasynaptic GABAA receptors. Positive allosteric modulatory Neurosteroids and synthetic analogs such as ganaxolone may be administered to prevent catamenial seizure exacerbations, in what we call neurosteroid replacement therapy.
Hubert Vaudry - One of the best experts on this subject based on the ideXlab platform.
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7α hydroxypregnenolone regulating locomotor behavior identified in the brain and pineal gland across vertebrates
General and Comparative Endocrinology, 2017Co-Authors: Kazuyoshi Tsutsui, Shogo Haraguchi, Hubert VaudryAbstract:Abstract The brain synthesizes steroids de novo from cholesterol, which are called Neurosteroids. Based on extensive studies on Neurosteroids over the past thirty years, it is now accepted that neurosteroidogenesis in the brain is a conserved property across vertebrates. However, the formation of bioactive Neurosteroids in the brain is still incompletely elucidated in vertebrates. In fact, we recently identified 7α-hydroxypregnenolone (7α-OH PREG) as a novel bioactive neurosteroid stimulating locomotor behavior in the brain of several vertebrates. The follow-up studies have demonstrated that the stimulatory action of brain 7α-OH PREG on locomotor behavior is mediated by the dopaminergic system across vertebrates. More recently, we have further demonstrated that the pineal gland, an endocrine organ located close to the brain, is a major site of the formation of bioactive Neurosteroids. In addition to the brain, the pineal gland actively produces 7α-OH PREG de novo from cholesterol as a major pineal neurosteroid that acts on the brain to control locomotor rhythms. This review summarizes the identification, biosynthesis and mode of action of brain and pineal 7α-OH PREG, a new bioactive neurosteroid regulating locomotor behavior, across vertebrates.
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RESEARCH ARTICLE The Non-Benzodiazepine Anxiolytic Drug Etifoxine Causes a Rapid, Receptor- Independent Stimulation of Neurosteroid
2016Co-Authors: Jean-luc Do Rego, David Vaudry, Hubert VaudryAbstract:Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxiety-like behaviors. The non-benzodiazepine anxiolytic compound etifoxine has been shown to increase neurosteroid concentrations in brain tissue but the mode of action of etifoxine on neurosteroid formation has not yet been elucidated. In the present study, we have thus in-vestigated the effect and the mechanism of action of etifoxine on neurosteroid biosynthesis using the frog hypothalamus as an experimental model. Exposure of frog hypothalamic explants to graded concentrations of etifoxine produced a dose-dependent increase in the biosynthesis of 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tet-rahydroprogesterone, associated with a decrease in the production of dihydroprogesterone. Time-course experiments revealed that a 15-min incubation of hypothalamic explants with etifoxine was sufficient to induce a robust increase in neurosteroid synthesis, suggesting that etifoxine activates steroidogenic enzymes at a post-translational level. Etifoxine-evoked neurosteroid biosynthesis was not affected by the central-type benzodiazepine (CBR) receptor antagonist flumazenil, the translocator protein (TSPO) antagonist PK1119
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the non benzodiazepine anxiolytic drug etifoxine causes a rapid receptor independent stimulation of neurosteroid biosynthesis
PLOS ONE, 2015Co-Authors: Jean-luc Do Rego, David Vaudry, Hubert VaudryAbstract:Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxiety-like behaviors. The non-benzodiazepine anxiolytic compound etifoxine has been shown to increase neurosteroid concentrations in brain tissue but the mode of action of etifoxine on neurosteroid formation has not yet been elucidated. In the present study, we have thus investigated the effect and the mechanism of action of etifoxine on neurosteroid biosynthesis using the frog hypothalamus as an experimental model. Exposure of frog hypothalamic explants to graded concentrations of etifoxine produced a dose-dependent increase in the biosynthesis of 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tetrahydroprogesterone, associated with a decrease in the production of dihydroprogesterone. Time-course experiments revealed that a 15-min incubation of hypothalamic explants with etifoxine was sufficient to induce a robust increase in neurosteroid synthesis, suggesting that etifoxine activates steroidogenic enzymes at a post-translational level. Etifoxine-evoked neurosteroid biosynthesis was not affected by the central-type benzodiazepine (CBR) receptor antagonist flumazenil, the translocator protein (TSPO) antagonist PK11195 or the GABAA receptor antagonist bicuculline. In addition, the stimulatory effects of etifoxine and the triakontatetraneuropeptide TTN, a TSPO agonist, were additive, indicating that these two compounds act through distinct mechanisms. Etifoxine also induced a rapid stimulation of neurosteroid biosynthesis from frog hypothalamus homogenates, a preparation in which membrane receptor signalling is disrupted. In conclusion, the present study demonstrates that etifoxine stimulates neurosteroid production through a membrane receptor-independent mechanism.
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the endozepine triakontatetraneuropeptide diazepam binding inhibitor 17 50 stimulates neurosteroid biosynthesis in the frog hypothalamus
Neuroscience, 1998Co-Authors: Jean Luc Dorego, Georges Pelletier, Marc G. J. Feuilloley, P Ferrara, A G Mensahnyagan, Hubert VaudryAbstract:Abstract Neurons and glial cells are capable of synthesizing various bioactive steroids, but the neuronal mechanisms controlling neurosteroid-secreting cells are poorly understood. In the present study, we have investigated the possible effect of an endogenous ligand of benzodiazepine receptors, the triakontatetraneuropeptide [17–50] (TTN), on steroid biosynthesis in the frog hypothalamus. Immunohistochemical studies revealed that most hypothalamic neurons expressing 3 β -hydroxysteroid dehydrogenase/ Δ 5 - Δ 4 -isomerase also contained peripheral-type benzodiazepine receptor-like immunoreactivity. Confocal laser scanning microscopic analysis revealed that the peripheral-type benzodiazepine receptor-immunoreactive material was located both in the cytoplasm and at the periphery of the cell bodies. By using the pulse-chase technique, TTN was found to stimulate the conversion of [ 3 H]pregnenolone into various steroids, including 17-hydroxypregnenolone, 5 α -dihydrotestosterone and 17-hydroxyprogesterone, in a dose-dependent manner. The peripheral-type benzodiazepine receptor agonist Ro5-4864 mimicked the stimulatory effect of TTN on the formation of Neurosteroids. The peripheral-type benzodiazepine receptor antagonist PK11195 significantly reduced the effect of TTN on neurosteroid synthesis, while the central-type benzodiazepine receptor antagonist flumazenil did not affect the formation of Neurosteroids evoked by TTN. These data indicate that TTN stimulates the biosynthesis of 3-keto-17 α -hydroxysteroids in frog hypothalamic neurons through activation of peripheral-type benzodiazepine receptors likely located at the plasma membrane level.
Steven Mennerick - One of the best experts on this subject based on the ideXlab platform.
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Neurosteroids as novel antidepressants and anxiolytics gaba a receptors and beyond
Neurobiology of Stress, 2019Co-Authors: Charles F. Zorumski, Douglas F. Covey, Steven M Paul, Steven MennerickAbstract:Abstract The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of Neurosteroids as modulators of brain function. This review considers potential mechanisms contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic Neurosteroids focusing on their actions as positive allosteric modulators of GABAA receptors. We also consider their roles as endogenous “stress” modulators and possible additional mechanisms contributing to their therapeutic effects. We argue that further understanding of the molecular, cellular, network and psychiatric effects of Neurosteroids offers the hope of further advances in the treatment of mood and anxiety disorders.
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Visualizing pregnenolone sulfate-like modulators of NMDA receptor function reveals intracellular and plasma-membrane localization
Neuropharmacology, 2019Co-Authors: Mariangela Chisari, Kathiresan Krishnan, Timothy J. Wilding, Samuel J. Brunwasser, Mingxing Qian, Ann Benz, James E. Huettner, Charles F. Zorumski, Douglas F. Covey, Steven MennerickAbstract:Positive modulators of NMDA receptors are important candidates for therapeutic development to treat psychiatric disorders including autism and schizophrenia. Sulfated Neurosteroids have been studied as positive allosteric modulators of NMDA receptors for years, but we understand little about the cellular fate of these compounds, an important consideration for drug development. Here we focus on a visualizable sulfated neurosteroid analogue, KK-169. As expected of a pregnenolone sulfate analogue, the compound strongly potentiates NMDA receptor function, is an antagonist of GABAA receptors, exhibits occlusion with pregnenolone sulfate potentiation, and requires receptor domains important for pregnenolone sulfate potentiation. KK-169 exhibits somewhat higher potency than the natural parent, pregnenolone sulfate. The analogue contains a side-chain alkyne group, which we exploited for retrospective click labeling of neurons. Although the anionic sulfate group is expected to hinder cell entry, we detected significant accumulation of KK-169 in neurons with even brief incubations. Adding a photolabile diazirine group revealed that the expected plasma membrane localization of KK-169 is likely lost during fixation. Overall, our studies reveal new facets of the structure-activity relationship of Neurosteroids at NMDA receptors, and their intracellular distribution suggests that sulfated Neurosteroids could have unappreciated targets in addition to plasma membrane receptors.
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a clickable neurosteroid photolabel reveals selective golgi compartmentalization with preferential impact on proximal inhibition
Neuropharmacology, 2016Co-Authors: Xiaoping Jiang, Kathiresan Krishnan, Mingxing Qian, Charles F. Zorumski, Hongjin Shu, Amanda Taylor, Steven MennerickAbstract:Anesthetic, GABA-active Neurosteroids potently augment GABAA receptor function, leading to important behavioral consequences. Neurosteroids and their synthetic analogues are also models for a wide variety of cell-permeant neuroactive compounds. Cell permeation and compartmentalization raise the possibility that these compounds' actions are influenced by their cellular partitioning, but these contributions are not typically considered experimentally or therapeutically. To examine the interplay between cellular accumulation and pharmacodynamics of Neurosteroids, we synthesized a novel chemical biology analogue (bio-active, clickable photolabel) of GABA-active Neurosteroids. We discovered that the analogue selectively photo-labels neuronal Golgi in rat hippocampal neurons. The active analogue's selective distribution was distinct from endogenous cholesterol and not completely shared by some non-GABA active, neurosteroid-like analogues. On the other hand, the distribution was not enantioselective and did not require energy, in contrast to other recent precedents from the literature. We demonstrate that the soma-selective accumulation can act as a sink or source for steroid actions at plasma-membrane GABA receptors, altering steady-state and time course of effects at somatic GABAA receptors relative to dendritic receptors. Our results suggest a novel mechanism for compartment-selective drug actions at plasma-membrane receptors.
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the neurosteroid 5β pregnan 3α ol 20 one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2l gabaa receptors
British Journal of Pharmacology, 2014Co-Authors: John Bracamontes, Steven Mennerick, Brad D Manion, Joseph H Steinbach, Alex S EversAbstract:Background and Purpose Neurosteroids potentiate responses of the GABAA receptor to the endogenous agonist GABA. Here, we examined the ability of Neurosteroids to potentiate responses to the allosteric activators etomidate, pentobarbital and propofol. Experimental Approach Electrophysiological assays were conducted on rat α1β2γ2L GABAA receptors expressed in HEK 293 cells. The sedative activity of etomidate was studied in Xenopus tadpoles and mice. Effects of Neurosteroids on etomidate-elicited inhibition of cortisol synthesis were determined in human adrenocortical cells. Key Results The neurosteroid 5β-pregnan-3α-ol-20-one (3α5βP) potentiated activation of GABAA receptors by GABA and allosteric activators. Co-application of 1 μM 3α5βP induced a leftward shift (almost 100-fold) of the whole-cell macroscopic concentration–response relationship for gating by etomidate. Co-application of 100 nM 3α5βP reduced the EC50 for potentiation by etomidate of currents elicited by 0.5 μM GABA by about three-fold. In vivo, 3α5βP (1mg kg-1) reduced the dose of etomidate required to produce loss of righting in mice (ED50) by almost 10-fold. In tadpoles, the presence of 50 or 100 nM 3α5βP shifted the EC50 for loss of righting about three- or ten-fold respectively. Exposure to 3α5βP did not influence inhibition of cortisol synthesis by etomidate. Conclusions and Implications Potentiating Neurosteroids act similarly on orthosterically and allosterically activated GABAA receptors. Co-application of Neurosteroids with etomidate can significantly reduce dosage requirements for the anaesthetic, and is a potentially beneficial combination to reduce undesired side effects.
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Neurosteroids stress and depression potential therapeutic opportunities
Neuroscience & Biobehavioral Reviews, 2013Co-Authors: Charles F. Zorumski, Douglas F. Covey, Steven M Paul, Yukitoshi Izumi, Steven MennerickAbstract:Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for γ-aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those Neurosteroids that potently modulate the function of GABAA receptors. We then discuss evidence indicating a role for GABA and Neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes.
Jean-luc Do Rego - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE The Non-Benzodiazepine Anxiolytic Drug Etifoxine Causes a Rapid, Receptor- Independent Stimulation of Neurosteroid
2016Co-Authors: Jean-luc Do Rego, David Vaudry, Hubert VaudryAbstract:Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxiety-like behaviors. The non-benzodiazepine anxiolytic compound etifoxine has been shown to increase neurosteroid concentrations in brain tissue but the mode of action of etifoxine on neurosteroid formation has not yet been elucidated. In the present study, we have thus in-vestigated the effect and the mechanism of action of etifoxine on neurosteroid biosynthesis using the frog hypothalamus as an experimental model. Exposure of frog hypothalamic explants to graded concentrations of etifoxine produced a dose-dependent increase in the biosynthesis of 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tet-rahydroprogesterone, associated with a decrease in the production of dihydroprogesterone. Time-course experiments revealed that a 15-min incubation of hypothalamic explants with etifoxine was sufficient to induce a robust increase in neurosteroid synthesis, suggesting that etifoxine activates steroidogenic enzymes at a post-translational level. Etifoxine-evoked neurosteroid biosynthesis was not affected by the central-type benzodiazepine (CBR) receptor antagonist flumazenil, the translocator protein (TSPO) antagonist PK1119
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the non benzodiazepine anxiolytic drug etifoxine causes a rapid receptor independent stimulation of neurosteroid biosynthesis
PLOS ONE, 2015Co-Authors: Jean-luc Do Rego, David Vaudry, Hubert VaudryAbstract:Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxiety-like behaviors. The non-benzodiazepine anxiolytic compound etifoxine has been shown to increase neurosteroid concentrations in brain tissue but the mode of action of etifoxine on neurosteroid formation has not yet been elucidated. In the present study, we have thus investigated the effect and the mechanism of action of etifoxine on neurosteroid biosynthesis using the frog hypothalamus as an experimental model. Exposure of frog hypothalamic explants to graded concentrations of etifoxine produced a dose-dependent increase in the biosynthesis of 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tetrahydroprogesterone, associated with a decrease in the production of dihydroprogesterone. Time-course experiments revealed that a 15-min incubation of hypothalamic explants with etifoxine was sufficient to induce a robust increase in neurosteroid synthesis, suggesting that etifoxine activates steroidogenic enzymes at a post-translational level. Etifoxine-evoked neurosteroid biosynthesis was not affected by the central-type benzodiazepine (CBR) receptor antagonist flumazenil, the translocator protein (TSPO) antagonist PK11195 or the GABAA receptor antagonist bicuculline. In addition, the stimulatory effects of etifoxine and the triakontatetraneuropeptide TTN, a TSPO agonist, were additive, indicating that these two compounds act through distinct mechanisms. Etifoxine also induced a rapid stimulation of neurosteroid biosynthesis from frog hypothalamus homogenates, a preparation in which membrane receptor signalling is disrupted. In conclusion, the present study demonstrates that etifoxine stimulates neurosteroid production through a membrane receptor-independent mechanism.
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neurosteroid biosynthesis enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides
Frontiers in Neuroendocrinology, 2009Co-Authors: Jae Young Seong, Van Luuthe, Jérôme Leprince, Jean-luc Do Rego, Kazuyoshi Tsutsui, Delphine Burel, Marie-christine TononAbstract:Neuroactive steroids synthesized in neuronal tissue, referred to as Neurosteroids, are implicated in proliferation, differentiation, activity and survival of nerve cells. Neurosteroids are also involved in the control of a number of behavioral, neuroendocrine and metabolic processes such as regulation of food intake, locomotor activity, sexual activity, aggressiveness, anxiety, depression, body temperature and blood pressure. In this article, we summarize the current knowledge regarding the existence, neuroanatomical distribution and biological activity of the enzymes responsible for the biosynthesis of Neurosteroids in the brain of vertebrates, and we review the neuronal mechanisms that control the activity of these enzymes. The observation that the activity of key steroidogenic enzymes is finely tuned by various neurotransmitters and neuropeptides strongly suggests that some of the central effects of these neuromodulators may be mediated via the regulation of neurosteroid production.
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Structure−Activity Relationships of a Series of Analogs of the Endozepine Octadecaneuropeptide (ODN 11 - 18 ) on Neurosteroid Biosynthesis by Hypothalamic Explants
'American Chemical Society (ACS)', 2007Co-Authors: Jean-luc Do Rego, Leprince Jérôme, Luu-the Van, Pelletier Georges, Tonon Marie-christine, Vaudry Hubert, Do Rego, Jean LucAbstract:International audienceWe have previously shown that the endozepine octadecaneuropeptide (ODN) stimulates the biosynthesis of Neurosteroids from frog hypothalamic explants. In the present study, we have investigated the structure-activity relationships of a series of analogs of the C-terminal octapeptide of ODN (OP) on neurosteroid formation. We found that OP and its cyclic analog cyclo1-8OP stimulate in a concentration-dependent manner the synthesis of various steroids including 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone and dehydroepiandrosterone. Deletion or Ala-substitution of the Arg1 or Pro2 residues of OP did not affect the activity of the peptide. In contrast, deletion or replacement of any of the amino acids of the C-terminal hexapeptide fragment totally abolished the effect of OP on neurosteroid biosynthesis. The present study indicates that the C-terminal hexapeptide of ODN/OP is the minimal sequence retaining full biological activity on steroid-producing neurons
Charles F. Zorumski - One of the best experts on this subject based on the ideXlab platform.
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Neurosteroids as novel antidepressants and anxiolytics gaba a receptors and beyond
Neurobiology of Stress, 2019Co-Authors: Charles F. Zorumski, Douglas F. Covey, Steven M Paul, Steven MennerickAbstract:Abstract The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of Neurosteroids as modulators of brain function. This review considers potential mechanisms contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic Neurosteroids focusing on their actions as positive allosteric modulators of GABAA receptors. We also consider their roles as endogenous “stress” modulators and possible additional mechanisms contributing to their therapeutic effects. We argue that further understanding of the molecular, cellular, network and psychiatric effects of Neurosteroids offers the hope of further advances in the treatment of mood and anxiety disorders.
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Visualizing pregnenolone sulfate-like modulators of NMDA receptor function reveals intracellular and plasma-membrane localization
Neuropharmacology, 2019Co-Authors: Mariangela Chisari, Kathiresan Krishnan, Timothy J. Wilding, Samuel J. Brunwasser, Mingxing Qian, Ann Benz, James E. Huettner, Charles F. Zorumski, Douglas F. Covey, Steven MennerickAbstract:Positive modulators of NMDA receptors are important candidates for therapeutic development to treat psychiatric disorders including autism and schizophrenia. Sulfated Neurosteroids have been studied as positive allosteric modulators of NMDA receptors for years, but we understand little about the cellular fate of these compounds, an important consideration for drug development. Here we focus on a visualizable sulfated neurosteroid analogue, KK-169. As expected of a pregnenolone sulfate analogue, the compound strongly potentiates NMDA receptor function, is an antagonist of GABAA receptors, exhibits occlusion with pregnenolone sulfate potentiation, and requires receptor domains important for pregnenolone sulfate potentiation. KK-169 exhibits somewhat higher potency than the natural parent, pregnenolone sulfate. The analogue contains a side-chain alkyne group, which we exploited for retrospective click labeling of neurons. Although the anionic sulfate group is expected to hinder cell entry, we detected significant accumulation of KK-169 in neurons with even brief incubations. Adding a photolabile diazirine group revealed that the expected plasma membrane localization of KK-169 is likely lost during fixation. Overall, our studies reveal new facets of the structure-activity relationship of Neurosteroids at NMDA receptors, and their intracellular distribution suggests that sulfated Neurosteroids could have unappreciated targets in addition to plasma membrane receptors.
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a clickable neurosteroid photolabel reveals selective golgi compartmentalization with preferential impact on proximal inhibition
Neuropharmacology, 2016Co-Authors: Xiaoping Jiang, Kathiresan Krishnan, Mingxing Qian, Charles F. Zorumski, Hongjin Shu, Amanda Taylor, Steven MennerickAbstract:Anesthetic, GABA-active Neurosteroids potently augment GABAA receptor function, leading to important behavioral consequences. Neurosteroids and their synthetic analogues are also models for a wide variety of cell-permeant neuroactive compounds. Cell permeation and compartmentalization raise the possibility that these compounds' actions are influenced by their cellular partitioning, but these contributions are not typically considered experimentally or therapeutically. To examine the interplay between cellular accumulation and pharmacodynamics of Neurosteroids, we synthesized a novel chemical biology analogue (bio-active, clickable photolabel) of GABA-active Neurosteroids. We discovered that the analogue selectively photo-labels neuronal Golgi in rat hippocampal neurons. The active analogue's selective distribution was distinct from endogenous cholesterol and not completely shared by some non-GABA active, neurosteroid-like analogues. On the other hand, the distribution was not enantioselective and did not require energy, in contrast to other recent precedents from the literature. We demonstrate that the soma-selective accumulation can act as a sink or source for steroid actions at plasma-membrane GABA receptors, altering steady-state and time course of effects at somatic GABAA receptors relative to dendritic receptors. Our results suggest a novel mechanism for compartment-selective drug actions at plasma-membrane receptors.
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metaplastic ltp inhibition after ltd induction in ca1 hippocampal slices involves nmda receptor mediated neurosteroidogenesis
Physiological Reports, 2013Co-Authors: Yukitoshi Izumi, Kazuko A Odell, Charles F. ZorumskiAbstract:Long-term depression (LTD) induced by low-frequency electrical stimulation (LFS) in the CA1 region of the hippocampus is a form of synaptic plasticity thought to contribute to learning and memory and to the pathophysiology of neuropsychiatric disorders. In naive hippocampal slices from juvenile rats, we previously found that LTD induction can impair subsequent induction of long-term potentiation (LTP) via a form of N-methyl-d-aspartate receptor (NMDAR)-dependent metaplasticity, and have recently observed that pharmacologically induced NMDAR-dependent LTP inhibition involves 5α-reduced Neurosteroids that augment the actions of γ-aminobutyric acid (GABA). In this study, we found that both LFS-induced LTD and subsequent inhibition of LTP induction involve neurosteroid synthesis via NMDAR activation. Furthermore, the timing of 5α-reductase inhibition relative to LFS can dissociate effects on LTD and metaplastic LTP inhibition. These findings indicate that 5α-reduced Neurosteroids play an important role in synaptic plasticity and synaptic modulation in the hippocampus.
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Neurosteroids stress and depression potential therapeutic opportunities
Neuroscience & Biobehavioral Reviews, 2013Co-Authors: Charles F. Zorumski, Douglas F. Covey, Steven M Paul, Yukitoshi Izumi, Steven MennerickAbstract:Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for γ-aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those Neurosteroids that potently modulate the function of GABAA receptors. We then discuss evidence indicating a role for GABA and Neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes.