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Doodipala Samba Reddy - One of the best experts on this subject based on the ideXlab platform.
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Catamenial-like seizure exacerbation in mice with targeted ablation of extrasynaptic δGABA-a receptors in the brain.
Journal of neuroscience research, 2017Co-Authors: Bryan L. Clossen, Doodipala Samba ReddyAbstract:Neurosteroids play a key role in catamenial epilepsy, a menstrual cycle-related seizure clustering in women with epilepsy. While Neurosteroids act on all GABA-A receptor isoforms, they cause greater effects on extrasynaptic δGABA-A receptors that mediate tonic inhibition in the brain. Previously, we identified a potential GABA-A receptor mechanism for catamenial epilepsy. However, the precise functional role of extrasynaptic δGABA-A receptors in the pathophysiology of catamenial epilepsy remains unclear. In this study, we utilized mice lacking extrasynaptic δGABA-A receptors (δKO) to investigate whether reduction of tonic inhibition affects catamenial seizure susceptibility or intensity. Intact female wildtype (WT) and δKO mice were subjected to hippocampus kindling until they exhibited stage 5 seizures. Elevated gonadal hormone-based Neurosteroid levels were induced by standard gonadotropin regimen and Neurosteroid withdrawal (NSW) was triggered by finasteride. NSW increased susceptibility to, as well the intensity of evoked catamenial-like seizures in WT and δKO mice. However, fully kindled δKO mice exhibited an accelerated and augmented response to NSW, with a more rapid increase in seizure susceptibility and intensity than WT mice undergoing the NSW paradigm. Moreover, δKO mice in NSW showed reduced benzodiazepine sensitivity, but in stark contrast to the increased Neurosteroid sensitivity observed in WT animals, δKO mice displayed no change in Neurosteroid sensitivity in response to NSW. The increased catamenial seizure exacerbation and alterations in antiseizure drug responses are consistent with NSW-induced changes in the abundance of δGABA-A receptors. Collectively, these findings provide evidence of a potential protective role for extrasynaptic δGABA-A receptors in catamenial-like seizures. © 2017 Wiley Periodicals, Inc.
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Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy
Frontiers in cellular neuroscience, 2016Co-Authors: Doodipala Samba ReddyAbstract:Catamenial epilepsy is a type of refractory epilepsy characterized by seizure clusters around perimenstrual or periovulatory period. The pathophysiology of catamenial epilepsy still remains unclear, yet there are few animal models to study this gender-specific disorder. The pathophysiology of perimenstrual catamenial epilepsy involves the withdrawal of the progesterone-derived GABAergic Neurosteroids due to the decline in progesterone level at the time of menstruation. These manifestations can be faithfully reproduced in rodents by specific neuroendocrine manipulations. Since mice and rats, like humans, have ovarian cycles with circulating hormones, they appear to be suitable animal models for studies of perimenstrual seizures. Recently, we created specific experimental models to mimic perimenstrual seizures. Studies in rat and mouse models of catamenial epilepsy show enhanced susceptibility to seizures or increased seizure exacerbations following Neurosteroid withdrawal. During such a seizure exacerbation period, there is a striking decrease in the anticonvulsant effect of commonly prescribed antiepileptics, such as benzodiazepines, but an increase in the anticonvulsant potency of exogenous Neurosteroids. We discovered an extrasynaptic molecular mechanism of catamenial epilepsy. In essence, extrasynaptic δGABA-A receptors are upregulated during perimenstrual-like neuroendocrine milieu. Consequently, there is enhanced antiseizure efficacy of Neurosteroids in catamenial models because δGABA-A receptors confer Neurosteroid sensitivity and greater seizure protection. Molecular mechanisms such as these offer a strong rationale for the clinical development of a Neurosteroid replacement therapy for catamenial epilepsy.
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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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Neurosteroids and Their Role in Sex-Specific Epilepsies
Neurobiology of Disease, 2014Co-Authors: Doodipala Samba ReddyAbstract: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 role for Neurosteroids in the pathophysiology of the sex-specific forms of epilepsies such as catamenial epilepsy, a menstrual cycle-related seizure disorder in women. Catamenial epilepsy is a neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around the perimenstrual or periovulatory period. Apart from ovarian hormones, fluctuations in Neurosteroid levels could play a critical role in this gender-specific epilepsy. Neurosteroids also regulate the plasticity of synaptic and extrasynaptic GABA-A receptors in the hippocampus and other regions involved in epilepsy pathology. Based on these studies, we proposed a Neurosteroid replacement therapy for catamenial epilepsy. Thus, Neurosteroids are novel drug targets for pharmacotherapy of epilepsy.
Hubert Vaudry - One of the best experts on this subject based on the ideXlab platform.
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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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Regulation of Neurosteroid Biosynthesis by Neurotransmitters and Neuropeptides
Frontiers in Endocrinology, 2012Co-Authors: Jean-luc Do Rego, Jae Young Seong, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Kazuyoshi Tsutsui, Delphine Burel, David Vaudry, Hubert VaudryAbstract: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 neurons as well as the neurotransmitter, peptide hormones, or neuropeptide receptors expressed in these neurons. Biochemical experiments have been conducted to investigate the effects of neurotransmitters, peptide hormones, or neuropeptides on Neurosteroid biosynthesis, and to characterize the type of receptors involved. Thus, it has been found that glutamate, acting through kainate and/or AMPA receptors, rapidly inactivates P450arom, and that melatonin produced by the pineal gland and eye inhibits the biosynthesis of 7α-hydroxypregnenolone (7α-OH-Δ(5)P), while prolactin produced by the adenohypophysis enhances the formation of 7α-OH-Δ(5)P. It has also been demonstrated that the biosynthesis of Neurosteroids is inhibited by GABA, acting through GABA(A) receptors, and neuropeptide Y, acting through Y1 receptors. In contrast, it has been shown that the octadecaneuropetide ODN, acting through central-type benzodiazepine receptors, the triakontatetraneuropeptide TTN, acting though peripheral-type benzodiazepine receptors, and vasotocin, acting through V1a-like receptors, stimulate the production of Neurosteroids. Since Neurosteroids are implicated in the control of various neurophysiological and behavioral processes, these data suggest that some of the neurophysiological effects exerted by neurotransmitters and neuropeptides may be mediated via the regulation of Neurosteroid production.
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The octadecaneuropeptide ODN stimulates Neurosteroid biosynthesis through activation of central‐type benzodiazepine receptors
Journal of neurochemistry, 2008Co-Authors: J.l. Do-rego, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Ayikoe Guy Mensah-nyagan, D Beaujean, Hubert VaudryAbstract:Neurosteroids may play a major role in the regulation of various neurophysiological and behavioural processes. However, while the biochemical pathways involved in the synthesis of neuroactive steroids in the central nervous system are now elucidated, the mechanisms controlling the activity of Neurosteroid-producing cells remain almost completely unknown. In the present study, we have investigated the effect of the octadecaneuropeptide (ODN), an endogenous ligand of benzodiazepine receptors, in the control of steroid biosynthesis in the frog hypothalamus. Glial cells containing ODN-like immunoreactivity were found to send their thick processes in the close vicinity of neurones expressing the steroidogenic enzyme 3β-hydroxysteroid dehydrogenase. Exposure of frog hypothalamic explants to graded concentrations of ODN (10−10−10−5m) produced a dose-dependent increase in the conversion of tritiated pregnenolone into various radioactive steroids, including 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone and dihydrotestosterone. The ODN-induced stimulation of Neurosteroid biosynthesis was mimicked by the central-type benzodiazepine receptor (CBR) inverse agonists methyl β-carboline-3-carboxylate (β-CCM) and methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). The stimulatory effects of ODN, β-CCM and DMCM on steroid formation was markedly reduced by the CBR antagonist flumazenil. The ODN-evoked stimulation of Neurosteroid production was also significantly attenuated by GABA. Collectively, these data indicate that the endozepine ODN, released by glial cell processes in the vicinity of 3β-hydroxysteroid dehydrogenase-containing neurones, stimulates the biosynthesis of Neurosteroids through activation of central-type benzodiazepines receptors.
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Structure-activity relationships of a series of analogs of the endozepine octadecaneuropeptide (ODN11- 18) on Neurosteroid biosynthesis by hypothalamic explants
Journal of medicinal chemistry, 2007Co-Authors: Jean-luc Do Rego, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Hubert VaudryAbstract:We 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.
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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
Journal of Medicinal Chemistry, 2007Co-Authors: Jean-luc Do Rego, Hubert Vaudry, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Jean-luc Do RegoAbstract:We 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.
Tzer Bin Lin - One of the best experts on this subject based on the ideXlab platform.
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Acute Neurosteroids inhibit the spinal reflex potentiation via GABAergic neurotransmission
American journal of physiology. Renal physiology, 2010Co-Authors: Junn Liang Chang, Hsien Yu Peng, Shwu Fen Pan, Mei Jung Chen, Tzer Bin LinAbstract:Recently, we demonstrated a chronic Neurosteroid-dependent inhibition of activity-dependent spinal reflex potentiation (SRP), but it remains unclear whether Neurosteroids acutely modulate SRP induc...
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Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABAA receptor subtypes
Pain, 2009Co-Authors: Hsien Yu Peng, Gin Den Chen, Shin-da Lee, Cheng Yuan Lai, Chun Hsien Chiu, Chen Li Cheng, Yu Shuo Chang, Ming Chun Hsieh, Kwong Chung Tung, Tzer Bin LinAbstract:Abstract Recently, we demonstrated a spinal GABA A receptor (GABA A R)-dependent inhibition on the induction of repetitive stimulation-induced spinal reflex potentiation. However, it remains unclear whether steroid hormones modulate such an inhibition. Here, we show that progesterone is capable of producing GABA A Rs-dependent inhibition of the induction of spinal reflex potentiation by actions through Neurosteroid metabolites. Progesterone (5 mg/kg, twice daily for 4 days) up-regulates the expression of GABA A R α2, α3, α4 and δ subunits, and is associated with attenuated repetitive stimulation-induced spinal reflex activity in ovariectomized rats. These changes were blocked by finasteride (50 mg/kg, twice daily), an antagonist of Neurosteroid synthesis from progesterone, but not by the progesterone receptor antagonist, RU486 (100 mg/kg, twice daily). The induction of spinal reflex potentiation was attenuated after a short (30 min) intrathecal treatment with the Neurosteroids, allopregnanolone (ALLOP, 10 μM, 10 μL) and 3α,5α-tetrahydrodeoxycorticosterone (THDOC, 10 μM, 10 μL). Acute intrathecal administration of the GABA A R antagonist, bicuculline (10 μM, 10 μL) reversed the inhibition produced by progesterone, THDOC and allopregnanolone. These results imply that progesterone-mediated effects on GABA A R expression and neural inhibition are regulated by Neurosteroids synthesis rather than progesterone receptor activation.
Hsien Yu Peng - One of the best experts on this subject based on the ideXlab platform.
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Acute Neurosteroids inhibit the spinal reflex potentiation via GABAergic neurotransmission
American journal of physiology. Renal physiology, 2010Co-Authors: Junn Liang Chang, Hsien Yu Peng, Shwu Fen Pan, Mei Jung Chen, Tzer Bin LinAbstract:Recently, we demonstrated a chronic Neurosteroid-dependent inhibition of activity-dependent spinal reflex potentiation (SRP), but it remains unclear whether Neurosteroids acutely modulate SRP induc...
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Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABA(A) receptor subtypes.
Pain, 2009Co-Authors: Hsien Yu Peng, Gin Den Chen, Shin-da Lee, Cheng Yuan Lai, Chun Hsien Chiu, Chen Li Cheng, Yu Shuo Chang, Ming Chun Hsieh, Kwong Chung Tung, Tzer-bin LinAbstract:Recently, we demonstrated a spinal GABA(A) receptor (GABA(A)R)-dependent inhibition on the induction of repetitive stimulation-induced spinal reflex potentiation. However, it remains unclear whether steroid hormones modulate such an inhibition. Here, we show that progesterone is capable of producing GABA(A)Rs-dependent inhibition of the induction of spinal reflex potentiation by actions through Neurosteroid metabolites. Progesterone (5mg/kg, twice daily for 4 days) up-regulates the expression of GABA(A)R alpha2, alpha3, alpha4 and delta subunits, and is associated with attenuated repetitive stimulation-induced spinal reflex activity in ovariectomized rats. These changes were blocked by finasteride (50mg/kg, twice daily), an antagonist of Neurosteroid synthesis from progesterone, but not by the progesterone receptor antagonist, RU486 (100mg/kg, twice daily). The induction of spinal reflex potentiation was attenuated after a short (30 min) intrathecal treatment with the Neurosteroids, allopregnanolone (ALLOP, 10 microM, 10 microL) and 3 alpha,5 alpha-tetrahydrodeoxycorticosterone (THDOC, 10 microM, 10 microL). Acute intrathecal administration of the GABA(A)R antagonist, bicuculline (10 microM, 10 microL) reversed the inhibition produced by progesterone, THDOC and allopregnanolone. These results imply that progesterone-mediated effects on GABA(A)R expression and neural inhibition are regulated by Neurosteroids synthesis rather than progesterone receptor activation.
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Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABAA receptor subtypes
Pain, 2009Co-Authors: Hsien Yu Peng, Gin Den Chen, Shin-da Lee, Cheng Yuan Lai, Chun Hsien Chiu, Chen Li Cheng, Yu Shuo Chang, Ming Chun Hsieh, Kwong Chung Tung, Tzer Bin LinAbstract:Abstract Recently, we demonstrated a spinal GABA A receptor (GABA A R)-dependent inhibition on the induction of repetitive stimulation-induced spinal reflex potentiation. However, it remains unclear whether steroid hormones modulate such an inhibition. Here, we show that progesterone is capable of producing GABA A Rs-dependent inhibition of the induction of spinal reflex potentiation by actions through Neurosteroid metabolites. Progesterone (5 mg/kg, twice daily for 4 days) up-regulates the expression of GABA A R α2, α3, α4 and δ subunits, and is associated with attenuated repetitive stimulation-induced spinal reflex activity in ovariectomized rats. These changes were blocked by finasteride (50 mg/kg, twice daily), an antagonist of Neurosteroid synthesis from progesterone, but not by the progesterone receptor antagonist, RU486 (100 mg/kg, twice daily). The induction of spinal reflex potentiation was attenuated after a short (30 min) intrathecal treatment with the Neurosteroids, allopregnanolone (ALLOP, 10 μM, 10 μL) and 3α,5α-tetrahydrodeoxycorticosterone (THDOC, 10 μM, 10 μL). Acute intrathecal administration of the GABA A R antagonist, bicuculline (10 μM, 10 μL) reversed the inhibition produced by progesterone, THDOC and allopregnanolone. These results imply that progesterone-mediated effects on GABA A R expression and neural inhibition are regulated by Neurosteroids synthesis rather than progesterone receptor activation.
Georges Pelletier - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Neurosteroid Biosynthesis by Neurotransmitters and Neuropeptides
Frontiers in Endocrinology, 2012Co-Authors: Jean-luc Do Rego, Jae Young Seong, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Kazuyoshi Tsutsui, Delphine Burel, David Vaudry, Hubert VaudryAbstract: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 neurons as well as the neurotransmitter, peptide hormones, or neuropeptide receptors expressed in these neurons. Biochemical experiments have been conducted to investigate the effects of neurotransmitters, peptide hormones, or neuropeptides on Neurosteroid biosynthesis, and to characterize the type of receptors involved. Thus, it has been found that glutamate, acting through kainate and/or AMPA receptors, rapidly inactivates P450arom, and that melatonin produced by the pineal gland and eye inhibits the biosynthesis of 7α-hydroxypregnenolone (7α-OH-Δ(5)P), while prolactin produced by the adenohypophysis enhances the formation of 7α-OH-Δ(5)P. It has also been demonstrated that the biosynthesis of Neurosteroids is inhibited by GABA, acting through GABA(A) receptors, and neuropeptide Y, acting through Y1 receptors. In contrast, it has been shown that the octadecaneuropetide ODN, acting through central-type benzodiazepine receptors, the triakontatetraneuropeptide TTN, acting though peripheral-type benzodiazepine receptors, and vasotocin, acting through V1a-like receptors, stimulate the production of Neurosteroids. Since Neurosteroids are implicated in the control of various neurophysiological and behavioral processes, these data suggest that some of the neurophysiological effects exerted by neurotransmitters and neuropeptides may be mediated via the regulation of Neurosteroid production.
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The octadecaneuropeptide ODN stimulates Neurosteroid biosynthesis through activation of central‐type benzodiazepine receptors
Journal of neurochemistry, 2008Co-Authors: J.l. Do-rego, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Ayikoe Guy Mensah-nyagan, D Beaujean, Hubert VaudryAbstract:Neurosteroids may play a major role in the regulation of various neurophysiological and behavioural processes. However, while the biochemical pathways involved in the synthesis of neuroactive steroids in the central nervous system are now elucidated, the mechanisms controlling the activity of Neurosteroid-producing cells remain almost completely unknown. In the present study, we have investigated the effect of the octadecaneuropeptide (ODN), an endogenous ligand of benzodiazepine receptors, in the control of steroid biosynthesis in the frog hypothalamus. Glial cells containing ODN-like immunoreactivity were found to send their thick processes in the close vicinity of neurones expressing the steroidogenic enzyme 3β-hydroxysteroid dehydrogenase. Exposure of frog hypothalamic explants to graded concentrations of ODN (10−10−10−5m) produced a dose-dependent increase in the conversion of tritiated pregnenolone into various radioactive steroids, including 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone and dihydrotestosterone. The ODN-induced stimulation of Neurosteroid biosynthesis was mimicked by the central-type benzodiazepine receptor (CBR) inverse agonists methyl β-carboline-3-carboxylate (β-CCM) and methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). The stimulatory effects of ODN, β-CCM and DMCM on steroid formation was markedly reduced by the CBR antagonist flumazenil. The ODN-evoked stimulation of Neurosteroid production was also significantly attenuated by GABA. Collectively, these data indicate that the endozepine ODN, released by glial cell processes in the vicinity of 3β-hydroxysteroid dehydrogenase-containing neurones, stimulates the biosynthesis of Neurosteroids through activation of central-type benzodiazepines receptors.
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Structure-activity relationships of a series of analogs of the endozepine octadecaneuropeptide (ODN11- 18) on Neurosteroid biosynthesis by hypothalamic explants
Journal of medicinal chemistry, 2007Co-Authors: Jean-luc Do Rego, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Hubert VaudryAbstract:We 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.
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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
Journal of Medicinal Chemistry, 2007Co-Authors: Jean-luc Do Rego, Hubert Vaudry, Georges Pelletier, Jérôme Leprince, Marie-christine Tonon, Van Luu-the, Jean-luc Do RegoAbstract:We 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.
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vasotocin and mesotocin stimulate the biosynthesis of Neurosteroids in the frog brain
The Journal of Neuroscience, 2006Co-Authors: Jean Luc Dorego, Sujata Acharjee, Jae Young Seong, Patrice Bizet, Hyuk Bang Kwon, Van Luuthe, Arlette Burlet, Ludovic Galas, David Alexandre, Georges PelletierAbstract:The neurohypophysial nonapeptides vasopressin (VP) and oxytocin (OT) modulate a broad range of cognitive and social activities. Notably, in amphibians, vasotocin (VT), the ortholog of mammalian VP, plays a crucial role in the control of sexual behaviors. Because several Neurosteroids also regulate reproduction-related behaviors, we investigated the possible effect of VT and the OT ortholog mesotocin (MT) in the control of Neurosteroid production. Double immunohistochemical labeling of frog brain sections revealed the presence of VT/MT-positive fibers in close proximity of neurons expressing the steroidogenic enzymes 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD) and cytochrome P450 17α-hydroxylase/c17, 20-lyase (P450C17). High concentrations of VT and MT receptor mRNAs were observed in diencephalic nuclei containing the 3β-HSD and P450C17 neuronal populations. Exposure of frog hypothalamic explants to graded concentrations of VT or MT produced a dose-dependent increase in the formation of progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone. The stimulatory effect of VT and MT on Neurosteroid biosynthesis was mimicked by VP and OT, as well as by a selective V1b receptor agonist, whereas V2 and OT receptor agonists had no effect. VT-induced Neurosteroid production was completely suppressed by selective V1a receptor antagonists and was not affected by V2 and OT receptor antagonists. Concurrently, the effect of MT on Neurosteroidogenesis was markedly attenuated by selective OT and V1a receptor antagonists but not by a V2 antagonist. The present study provides the first evidence for a regulatory effect of VT and MT on Neurosteroid biosynthesis. These data suggest that Neurosteroids may mediate some of the behavioral actions of VT and MT.