GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo.
01 Jun 2016-The Journal of Steroid Biochemistry and Molecular Biology (J Steroid Biochem Mol Biol)-Vol. 160, pp 98-105
TL;DR: It is shown that pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice and that 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation of the GABAA receptor.
About: This article is published in The Journal of Steroid Biochemistry and Molecular Biology.The article was published on 2016-06-01 and is currently open access. It has received 29 citations till now. The article focuses on the topics: Allopregnanolone & Tetrahydrodeoxycorticosterone.
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TL;DR: This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease.
160 citations
Virginia Commonwealth University1, University of Michigan2, University of Pittsburgh3, Baylor University Medical Center4, University of Alberta5, University of Cambridge6, Paris-Sorbonne University7, Post Graduate Institute of Medical Education and Research8, University of Seville9, University of Padua10
TL;DR: Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management, and a consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice.
70 citations
TL;DR: It is suggested that adrenal steroids upregulated by etifoxine make an important contribution to the steroids present in brain, and this work provides a precise and complete view of steroids regulated by et ifoxine that could be useful in therapeutic research.
27 citations
Cites background from "GABAA receptor modulating steroid a..."
...3β,5α-THP is now recognized as a member of a novel class of GABAA receptor modulating steroid antagonists (GAMSA) (Johansson et al., 2016), thus offering new therapeutic approaches for enhancement of brain excitability....
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TL;DR: Golexanolone as mentioned in this paper is a small molecule GABA-A receptor modulating steroid antagonist under development for treatment of cognitive and vigilance disorders due to allosteric over-activation of GABA receptors by neurosteroids.
21 citations
TL;DR: In this paper, the effects of stigmasterol, a plant sterol (phytosterol) isolated from Artemisia indica Linn on neurological disorders, were investigated on various recombinant GABAA receptor subtypes expressed in Xenopus laevis oocytes.
19 citations
References
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TL;DR: Two metabolites of the steroid hormones progesterone and deoxycorticosterone are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons, which may explain the ability of certain steroid hormones to rapidly alter neuronal excitability.
Abstract: Two metabolites of the steroid hormones progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone and 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone, are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex. At concentrations between 10(-7) and 10(-5)M both steroids inhibited binding of the convulsant t-butylbicyclophosphorothionate to the GABA-receptor complex and increased the binding of the benzodiazepine flunitrazepam; they also stimulated chloride uptake (as measured by uptake of 36Cl-) into isolated brain vesicles, and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons. These data may explain the ability of certain steroid hormones to rapidly alter neuronal excitability and may provide a mechanism for the anesthetic and hypnotic actions of naturally occurring and synthetic anesthetic steroids.
2,175 citations
"GABAA receptor modulating steroid a..." refers background in this paper
...In contrast, GABAA receptor antagonists directed against the GABA site, like bicuculline, or chloride channel blockers such as picrotoxin, or the GABAA receptor negative allosteric modulator pregnenolone sulfate block both the effect of GABA and allopregnanolone/THDOC potentiation of the receptor [45,42,29]....
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...In hippocampal neurons allopregnanolone increases both the peak amplitude and duration of chloride currents induced by GABA [45]....
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...Endogenous steroids, including allopregnanolone (3a-hydroxy-5a-pregnan-20-one) and THDOC (3a,5a-tetrahydrodeoxycorticosterone) are positive allosteric GABAA receptor modulators [45],Fig....
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TL;DR: The presence of allopregnanolone and allotetrahydroDOC in brain is demonstrated and acute stress results in a rapid increase of these neuroactive steroids to levels known to modulate GABAA receptor function.
Abstract: A 3 alpha-hydroxy A-ring-reduced metabolite of progesterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone), and one of deoxycorticosterone (DOC), 3 alpha,21-dihydroxy-5 alpha-pregnan-20- one (allotetrahydroDOC), are among the most potent known ligands of gamma-aminobutyric acid (GABA) receptors designated GABAA in the central nervous system. With specific radioimmunoassays, rapid (less than 5 min) and robust (4- to 20-fold) increases of allopregnanolone and allotetrahydroDOC were detected in the brain (cerebral cortex and hypothalamus) and in plasma of rats after exposure to ambient temperature swin stress. Neither steroid was detectable in the plasma of adrenalectomized rats either before or after swim stress. However, allopregnanolone, but not allotetrahydroDOC, was still present in the cerebral cortex (greater than 3 ng/g) after adrenalectomy. These data demonstrate the presence of allopregnanolone and allotetrahydroDOC in brain and show that acute stress results in a rapid increase of these neuroactive steroids to levels known to modulate GABAA receptor function.
917 citations
TL;DR: Two discrete binding sites in the GABAA receptor’s transmembrane domains are identified that mediate the potentiating and direct activation effects of neurosteroids and provide a unique opportunity for the development of new therapeutic, neurosteroid-based ligands and transgenic disease models of Neurosteroid dysfunction.
Abstract: Inhibitory neurotransmission mediated by GABA(A) receptors can be modulated by the endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone(1). Neurosteroids are synthesized de novo in the brain during stress(2), pregnancy(3) and after ethanol consumption(4), and disrupted steroid regulation of GABAergic transmission is strongly implicated in several debilitating conditions such as panic disorder, major depression, schizophrenia, alcohol dependence and catamenial epilepsy(3,5-8). Determining how neurosteroids interact with the GABA(A) receptor is a prerequisite for understanding their physiological and pathophysiological roles in the brain. Here we identify two discrete binding sites in the receptor's transmembrane domains that mediate the potentiating and direct activation effects of neurosteroids. They potentiate GABA responses from a cavity formed by the alpha-subunit transmembrane domains, whereas direct receptor activation is initiated by interfacial residues between alpha and beta subunits and is enhanced by steroid binding to the potentiation site. Thus, significant receptor activation by neurosteroids relies on occupancy of both the activation and potentiation sites. These sites are highly conserved throughout the GABA(A) receptor family, and their identification provides a unique opportunity for the development of new therapeutic, neurosteroid-based ligands and transgenic disease models of neurosteroid dysfunction.
673 citations
TL;DR: The data suggest that the anxiolytic effect of 3α-hydroxy metabolites of progesterone is mediated by brain GABAA receptors in a stereospecific manner, and are in good agreement with the well-documented in vitro effects of these steroids as potent modulators of the GabAA receptor.
443 citations
TL;DR: The data indicate that the pregnane steroids produce their anxiolytic effects through a separate mechanism than the BZs, and demonstrate that the endogenous pregnano steroids possess anxioleytic effects that may be clinically relevant.
305 citations