Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor
In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). These reports were followed by the discovery that such steroids may be synthesised not only in peri...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Neurobiology of Stress |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352289519300591 |
| _version_ | 1819140249615335424 |
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| author | Delia Belelli Derk Hogenkamp Kelvin W. Gee Jeremy J. Lambert |
| author_facet | Delia Belelli Derk Hogenkamp Kelvin W. Gee Jeremy J. Lambert |
| author_sort | Delia Belelli |
| collection | DOAJ |
| description | In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). 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 GABAAR-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. |
| first_indexed | 2024-12-22T11:35:33Z |
| format | Article |
| id | doaj.art-8b28a0f5a73447948d30996d5d43b0e6 |
| institution | Directory Open Access Journal |
| issn | 2352-2895 |
| language | English |
| last_indexed | 2024-12-22T11:35:33Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Stress |
| spelling | doaj.art-8b28a0f5a73447948d30996d5d43b0e62022-12-21T18:27:27ZengElsevierNeurobiology of Stress2352-28952020-05-0112Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptorDelia Belelli0Derk Hogenkamp1Kelvin W. Gee2Jeremy J. Lambert3Systems Medicine, Neuroscience, Mail Box 6, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United KingdomDepartment of Pharmacology, 110C Med Surge1, Mail Code 4625, University of California, Irvine, School of Medicine, Irvine, CA, 92697, USADepartment of Pharmacology, 110C Med Surge1, Mail Code 4625, University of California, Irvine, School of Medicine, Irvine, CA, 92697, USASystems Medicine, Neuroscience, Mail Box 6, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom; Corresponding author.In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). 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 GABAAR-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.http://www.sciencedirect.com/science/article/pii/S2352289519300591AllopregnanoloneGABAA receptorNeurosteroidPhasic inhibitionTonic inhibition |
| spellingShingle | Delia Belelli Derk Hogenkamp Kelvin W. Gee Jeremy J. Lambert Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor Neurobiology of Stress Allopregnanolone GABAA receptor Neurosteroid Phasic inhibition Tonic inhibition |
| title | Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor |
| title_full | Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor |
| title_fullStr | Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor |
| title_full_unstemmed | Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor |
| title_short | Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor |
| title_sort | realising the therapeutic potential of neuroactive steroid modulators of the gabaa receptor |
| topic | Allopregnanolone GABAA receptor Neurosteroid Phasic inhibition Tonic inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S2352289519300591 |
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