Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California Los Angeles, CA, USA.
Front Endocrinol (Lausanne). 2012 Jan 12;2:117. doi: 10.3389/fendo.2011.00117. eCollection 2011.
The proliferative pool and regenerative potential of neural stem cells diminishes with age, a phenomenon that may be exacerbated in prodromal and mild Alzheimer's disease (AD) brains. In parallel, the neuroactive progesterone metabolite, allopregnanolone (APα), along with a host of other factors, is decreased in the AD brain. Results of preclinical analyses demonstrate that APα is a potent inducer of neural progenitor proliferation of both rodent and human derived neural progenitor cells in vitro. In vivo, APα significantly increased neurogenesis within the subgranular zone of the dentate gyrus and subventricular zone of the 3xTgAD mouse model. Functionally, APα reversed the learning and memory deficits of 3xTgAD mice prior to and following the onset of AD pathology and was comparably efficacious in aged normal mice. In addition to inducing regenerative responses in mouse models of AD, APα significantly reduced beta-amyloid burden, beta-amyloid binding alcohol dehydrogenase load, and microglial activation. In parallel, APα increased markers of white matter generation and cholesterol homeostasis. Analyses to determine the optimal treatment regimen in the 3xTgAD mouse brain indicated that a treatment regimen of APα once per week was optimal for both inducing neurogenesis and reducing AD pathology. Pharmacokinetic analyses indicated that APα is rapidly increased in both plasma and brain following a single dose. APα is most efficacious when administered once per week which will contribute to its margin of safety. Further, analyses in both animals and humans have provided parameters for safe APα dosage exposure in humans. From a translational perspective, APα is a small molecular weight, blood brain barrier penetrant molecule with substantial preclinical efficacy data as a potential Alzheimer's therapeutic with existing safety data in animals and humans. To our knowledge, APα is the only small molecule that both promotes neural progenitor regeneration in brain and simultaneously reduces AD pathology burden.
神经干细胞的增殖池和再生潜能随着年龄的增长而减少，这种现象在前驱期和轻度阿尔茨海默病（AD）大脑中可能会加剧。与此同时，神经活性孕酮代谢物，别孕烯醇酮（APα）以及许多其他因素，在 AD 大脑中减少。临床前分析的结果表明，APα 是体外啮齿动物和人源性神经祖细胞增殖的有效诱导剂。在体内，APα 显著增加了 3xTgAD 小鼠模型齿状回颗粒下区和脑室下区的神经发生。功能上，APα 在 AD 病理发生之前和之后逆转了 3xTgAD 小鼠的学习和记忆缺陷，并且在老年正常小鼠中同样有效。除了在 AD 小鼠模型中诱导再生反应外，APα 还显著降低了β-淀粉样蛋白负担、β-淀粉样蛋白结合醇脱氢酶负荷和小胶质细胞激活。平行地，APα 增加了白质生成和胆固醇稳态的标志物。确定 3xTgAD 小鼠大脑中最佳治疗方案的分析表明，APα 每周一次的治疗方案对于诱导神经发生和减少 AD 病理都是最佳的。药代动力学分析表明，APα 在单次给药后迅速增加血浆和大脑中的浓度。APα 每周一次给药最有效，这将有助于提高其安全性。此外，在动物和人类中的分析为人类提供了安全的 APα 剂量暴露参数。从转化的角度来看，APα 是一种具有小分子重量、血脑屏障通透性的分子，具有大量的临床前疗效数据，是一种有潜力的阿尔茨海默病治疗药物，在动物和人类中已有安全性数据。据我们所知，APα 是唯一一种既能促进大脑神经祖细胞再生，又能同时减轻 AD 病理负担的小分子。
