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

Abstract

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.

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling

“…We next sought to investigate whether progesterone and its metabolite allopregnanolone influence avoidance behavior. Diestrus mice were administered either vehicle, asoprisnil: a selective progesterone receptor modulator with primarily antagonistic action (DeManno et al, 2003), or sepranolone: a negative allosteric modulator of allopregnanolone’s GABA A R binding site (Bäckström et al, 2021), before being tested on the EPM and the open field. After vehicle administration, MSEW diestrus mice spent significantly less time in the open arms than control mice (Drug x MSEW: F 2,44 = 13.00, p < 0.0001; Sidak’s multiple comparisons test control–MSEW vehicle p = 0.0163) (Fig.…”

“…We next sought to investigate whether progesterone and its metabolite allopregnanolone influence avoidance behavior. Diestrus mice were administered either vehicle, asoprisnil: a selective progesterone receptor modulator with primarily antagonistic action (DeManno et al, 2003), or sepranolone: a negative allosteric modulator of allopregnanolone's GABAAR binding site (Bäckström et al, 2021) Administration of either asoprisnil or sepranolone abolished the difference in grooming time between control and MSEW mice (Sidak's multiple comparisons test asoprisnil control-MSEW p = 0.9820; Sidak's multiple comparisons test sepranolone control-MSEW p = 0.9988) (Fig. 5c).…”

Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine

“…PROG metabolites, namely 3α, 5α-tetrahydroprogesterone (P3α5α, allopregnanolone), were later considered as barbiturate-like modulators of the γ-aminobutyric acid type A (GABA A ) receptor [ 69 ]. This work initiated intensive research into the effects of neuroactive steroids on GABA A receptors [ 70 , 71 , 72 , 73 , 74 , 75 ]. Furthermore, effects of neuroactive steroids on glycine [ 76 ], N-methyl- d -aspartate (NMDA) [ 77 , 78 ], nicotinic acetylcholine receptors [ 79 ] or G-protein coupled receptors [ 80 ] have also been found.…”

Neuroactive steroids: From basic research to clinical use

“…Probably the most studied mechanism of action of neuroactive steroids is the interaction with the GABA A receptor, 6 which has the possibility of influencing a wide number of circuits, functions and behavior. In humans, 7,8 elevated allopregnanolone levels are associated with disorders such as catamenial epilepsy, premenstrual disorder, hepatic encephalopathy, polycystic ovarian syndrome, increased negative mood, disturbed memory and increased food intake in some individuals. The review by Belelli et al 6 provides a history of the discovery and properties of interactions among neuroactive steroids and GABA A receptor, highlighting the difficulties found in clinical applications.…”

“…In a phase II clinical trial, Backstrom et al 7 demonstrated that injections of an analog of allopregnanolone, isoallopregnanolone, significantly ameliorated negative mood in women with premenstrual disorder compared to placebo. Other analogs may improve vigilance, cognition and pathological electroencephalogram in patients with hepatic encephalopathy.…”