Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments

GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABAA receptor modulating steroid with potent effects. In humans,...

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Published in:Journal of neuroendocrinology Vol. 34; no. 2; pp. e13013 - n/a
Main Authors: Bäckström, Torbjörn, Das, Roshni, Bixo, Marie
Format: Journal Article
Language:English
Published: Oxford Wiley Subscription Services, Inc 01.02.2022
Subjects:
allopregnanolone
Anesthesia
Benzodiazepines
Cognition
EEG
Food intake
GABAA receptor modulating steroid antagonists
Hepatic encephalopathy
Hyperactivity
isoallopregnanolone
Liver
Memory
Mood
Motor skill learning
Oral administration
Polycystic ovary syndrome
Pregnanolone
Progesterone
Saccadic eye movements
Steroid hormones
Steroids
Vigilance
γ-Aminobutyric acid A receptors
ISSN:0953-8194, 1365-2826, 1365-2826
Online Access:Get full text
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Summary:GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABAA receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti‐depressant. However, it is well established that, in certain individuals, GABAA receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3β‐OH sibling of Allo, functions as a GABAA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABAA receptors. The antagonistic effect is noted in most GABAA subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo‐induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABAA system. GABA is the major inhibitory moderating system in the CNS. GABA binds its receptor and allows Cl‐ ions flow through the receptor in or out of the neuron. GAMS causes an amplification of the Cl‐ flow that causes symptoms. GAMSA binds to its receptor and counteracts the GAMS amplification of GABA and by that decrease symptoms.
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ISSN:0953-8194
1365-2826
1365-2826
DOI:10.1111/jne.13013