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Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor

In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA(A) receptor (GABA(A)R). These reports were followed by the discovery that such steroids may be synthesised not only in...

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Autores principales: Belelli, Delia, Hogenkamp, Derk, Gee, Kelvin W., Lambert, Jeremy J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231973/
https://www.ncbi.nlm.nih.gov/pubmed/32435660
http://dx.doi.org/10.1016/j.ynstr.2019.100207
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author Belelli, Delia
Hogenkamp, Derk
Gee, Kelvin W.
Lambert, Jeremy J.
author_facet Belelli, Delia
Hogenkamp, Derk
Gee, Kelvin W.
Lambert, Jeremy J.
author_sort Belelli, Delia
collection PubMed
description In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA(A) receptor (GABA(A)R). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine “neurosteroid” messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABA(A)R-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders.
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spelling pubmed-72319732020-05-20 Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor Belelli, Delia Hogenkamp, Derk Gee, Kelvin W. Lambert, Jeremy J. Neurobiol Stress Articles from the Special Issue on Allopregnanolone role in the neurobiology of stress and mood disorders; Edited by Graziano Pinna In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA(A) receptor (GABA(A)R). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine “neurosteroid” messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABA(A)R-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders. Elsevier 2019-12-23 /pmc/articles/PMC7231973/ /pubmed/32435660 http://dx.doi.org/10.1016/j.ynstr.2019.100207 Text en © 2019 Published by Elsevier Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Articles from the Special Issue on Allopregnanolone role in the neurobiology of stress and mood disorders; Edited by Graziano Pinna
Belelli, Delia
Hogenkamp, Derk
Gee, Kelvin W.
Lambert, Jeremy J.
Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor
title Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor
title_full Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor
title_fullStr Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor
title_full_unstemmed Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor
title_short Realising the therapeutic potential of neuroactive steroid modulators of the GABA(A) receptor
title_sort realising the therapeutic potential of neuroactive steroid modulators of the gaba(a) receptor
topic Articles from the Special Issue on Allopregnanolone role in the neurobiology of stress and mood disorders; Edited by Graziano Pinna
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231973/
https://www.ncbi.nlm.nih.gov/pubmed/32435660
http://dx.doi.org/10.1016/j.ynstr.2019.100207
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