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_A 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_A 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_A receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABA_A receptors. The antagonistic effect is noted in most GABA_A 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_A system.

中文翻译：

---

阳性 GABAA 受体调节类固醇及其拮抗剂：对临床治疗的意义

GABA 是大脑中的主要抑制性神经递质，GABA 能传递已被证明对调节情绪、记忆和食物摄入很重要。孕酮代谢物异孕酮 (Allo) 是一种阳性 GABA _A受体调节类固醇，具有强效作用。在人类中，诸如经前烦躁症 (PMDD)、肝性脑病和多囊卵巢综合征等疾病与 Allo 水平升高和某些个体的负面情绪增加、记忆障碍和食物摄入增加有关。这是令人惊讶的，因为 Allo 与苯二氮卓类药物具有许多共同特性，并且主要被认为是抗焦虑和抗抑郁药。然而，众所周知，在某些个体中，GABA _A受体激活化合物可能具有自相矛盾的作用，因此在低生理血浆浓度时会产生焦虑，但在高水平时会产生抗焦虑作用。我们已经证明异丙孕烯醇酮 (Isoallo) 是 Allo 的 3β-OH 同胞，可作为 GABA _A受体调节类固醇拮抗剂 (GAMSA) 发挥作用，但其自身对 GABA _A受体没有任何影响。_{大多数 GABA A}都存在拮抗作用迄今为止在体外研究的亚型。在体内，Isoallo 可以抑制大鼠的 Allo 诱导的麻醉，以及人类的镇静作用或扫视速度。已在患有 PMDD 的女性中研究了 Isoallo 治疗。在第一个 II 期研究中，与安慰剂相比，Isoallo（Sepranolone；Asarina Pharma）注射剂显着改善了 PMDD 女性的负面情绪。还开发了几种用于口服给药的 GAMSA。GAMSA UC1011 可以抑制 Allo 引起的大鼠记忆障碍，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，用 GR3027 治疗的肝性脑病患者的警觉性、认知和病理脑电图得到改善。_一个系统。