Department of Clinical Sciences, University of Umeå, Umeå, Sweden.
Umecrine Cognition AB, Solna, Sweden.
J Intern Med. 2023 Sep;294(3):281-294. doi: 10.1111/joim.13705. Epub 2023 Jul 30.
The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.
认知功能障碍、痴呆和神经退行性疾病（如阿尔茨海默病[AD]）的患病率随着人口老龄化而同步增加。人们认为，中枢神经系统（CNS）疾病中不同类型的慢性应激是导致认知障碍的重要因素，而认知障碍是一种未满足的主要医疗需求。GABA 能神经传递亢进是应激效应的中介，但也是 CNS 疾病中其他因素的结果。正性 GABA-A 受体调节应激和性激素（类固醇-PAMs），如孕烷醇酮（ALLO）和醋酸甲地孕酮，可引起认知障碍。因此，ALLO 会损害动物和人类的记忆和学习能力。在转基因 AD 动物研究中，生理水平的 ALLO 持续暴露会损害认知功能并增加 AD 退行性病变，而间歇性 ALLO 注射则会增强认知功能，表明 ALLO 具有多效功能。我们已经表明，GABA-A 受体调节类固醇拮抗剂（GAMSAs）可以阻断 ALLO 在动物研究和肝性脑病引起认知障碍患者中的急性负性认知损害。在这里，我们描述了受类固醇-PAMs 影响的疾病，并描述了用新型 GAMSAs 治疗这些类固醇-PAMs 的不良反应的机会。
