Neuroregenerative mechanisms of allopregnanolone in Alzheimer's disease.
Neuroregenerative mechanisms of allopregnanolone in Alzheimer's disease.
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DOI：
10.3389/fendo.2011.00117
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发表时间：
2011
影响因子：
5.2
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Irwin RW;Wang JM;Chen S;Brinton RD
神经干细胞的增殖池和再生潜力随着年龄的增长而减少，这一现象在前驱症状和轻度阿尔茨海默病(AD)大脑中可能会加剧。同时，神经活性孕酮代谢物别孕酮(APα)与许多其他因素一起，在AD大脑中减少。临床前分析结果表明，AP-α在体外对啮齿类和人源性神经前体细胞均有较强的神经前体细胞增殖诱导作用。在体内，APα显著增加3xTgAD小鼠模型齿状回颗粒下带和脑室下带内的神经发生。在功能上，APα逆转了3xTgAD小鼠在AD病理发生前后的学习记忆障碍，对老年正常小鼠同样有效。除了在AD小鼠模型中诱导再生反应外，APα还显著降低了β-淀粉样蛋白负荷、β-淀粉样蛋白结合酒精脱氢酶负荷和小胶质细胞激活。同时，APα增加了白质生成和胆固醇稳态的标志物。在3xTgAD小鼠脑内确定最佳治疗方案的分析表明，每周一次的APα治疗方案在诱导神经发生和减轻AD病理方面都是最佳的。药代动力学分析表明，单次给药后，AP-α在血浆和脑内均迅速升高。APα每周给药一次是最有效的，这将有助于其安全边际。此外，在动物和人类中的分析为人类安全的APα剂量暴露提供了参数。从翻译的角度来看，APα是一种小分子、血脑屏障穿透性分子，具有大量的临床前疗效数据，可作为潜在的阿尔茨海默氏症治疗药物，现有的动物和人类安全性数据。据我们所知，APα是唯一一种既能促进脑内神经前体细胞再生又能减轻AD病理负担的小分子。
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.