Bengtsson S K S, Bäckström T, Brinton R, Irwin R W, Johansson M, Sjöstedt J, Wang M D
Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Sweden.
Center for Innovation in Brain Science, Professor Departments of Pharmacology and Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA.
Neurobiol Stress. 2019 Dec 20;12:100206. doi: 10.1016/j.ynstr.2019.100206. eCollection 2020 May.
Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.
随着全球人口老龄化，认知功能障碍、痴呆症和阿尔茨海默病（AD）的发病率正在上升。针对这些病症的治疗方法仍未满足需求。本综述聚焦于正向GABA-A受体调节类固醇别孕烯醇酮（APα）的作用、其在认知受损和AD潜在机制中的作用，以及确定AD的治疗方案。一方面，间歇性给予APα可促进神经发生、减少AD相关病理并改善认知。另一方面，持续暴露于APα会损害认知并使AD病理恶化。这两种结果之间的差异促使我们团队分析其背后的机制。我们得出结论，APα的作用取决于给药模式，长期轻度增加APα暴露对认知功能有害并会使AD病理恶化，而间隔较长时间的单次给药则可改善认知并减少AD病理。这些合作评估为AD的APα和APα拮抗剂的治疗开发提供了见解，并为旨在生成可转化为人体临床试验数据的跨实验室合作提供了模型。
