Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umea, Sweden.
Department of Integrative Medical Biology, Umeå University, Umea, Sweden.
J Neuroendocrinol. 2022 Feb;34(2):e13013. doi: 10.1111/jne.13013. Epub 2021 Aug 1.
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 GABA 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, GABA 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 GABA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABA receptors. The antagonistic effect is noted in most GABA 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 GABA system.
GABA 是大脑中的主要抑制性神经递质，已经证明 GABA 能传递对于调节情绪、记忆和食物摄入很重要。孕激素代谢产物孕烷醇酮（Allo）是一种具有强大作用的阳性 GABA 受体调制类固醇。在人类中，经前烦躁障碍（PMDD）、肝性脑病和多囊卵巢综合征等疾病与 Allo 水平升高以及一些个体中负面情绪增加、记忆障碍和食物摄入增加有关。这令人惊讶，因为 Allo 与苯二氮䓬类药物有许多共同特性，主要被认为是抗焦虑和抗抑郁药。然而，已经证实，在某些个体中，激活 GABA 受体的化合物可能会产生矛盾的作用，因此在低生理血浆浓度下具有焦虑作用，但在高浓度下具有抗焦虑作用。我们已经证明，异孕烷醇酮（Isoallo），Allo 的 3β-OH 同源物，作为 GABA 受体调制类固醇拮抗剂（GAMSA）起作用，但对 GABA 受体本身没有任何作用。迄今为止，在体外研究的大多数 GABA 亚型中都注意到了这种拮抗作用。在体内，Isoallo 可以抑制大鼠中 Allo 诱导的麻醉，以及人类中的镇静或扫视眼速度。Isoallo 治疗已在 PMDD 女性中进行了研究。在一项 I 期临床试验中，与安慰剂相比，Isoallo（Sepranolone；Asarina Pharma）注射显著改善了 PMDD 女性的负面情绪。还开发了几种口服 GAMSAs。GAMSA，UC1011，可以抑制大鼠中 Allo 诱导的记忆障碍，口服 GAMSA，GR3027，已被证明可以恢复肝性脑病大鼠的学习和运动协调能力。在人类中，肝性脑病患者接受 GR3027 治疗后警觉性、认知和病理性脑电图得到改善。总之，GAMSAs 是治疗 GABA 系统过度活跃引起的疾病和症状的一种新的可能治疗方法。
