2012年12月4日讯 /生物谷BIOON/ --明尼苏达大学药物设计中心的研究人员，开发出了一种人工合成化合物，该化合物在小鼠模型中，成功阻止了与阿尔茨海默氏症（Alzheimer's disease，AD）相关的神经退行性病变（neurodegeneration），为阿尔茨海默氏症及相关疾病的药物设计指明了一个新靶标。
在临床前研究中，研究人员发现，一种名为psi-GSH的实验室合成化合物，使大脑能够利用自身的保护酶系统——乙二醛酶（glyoxalase）阻止阿尔茨海默氏症疾病进程。研究结果已在线发表于ACS Chemical Neuroscience期刊。
“尽管大多数在研及已上市药物试图减缓或逆转阿尔茨海默氏症的进程，我们的方法却使大脑能够利用自身的酶系统在极早期阶段抗击疾病，”药物设计中心主任Vince说道。
此前科学家已发现，阿尔茨海默氏症能损害大脑利用乙二醛酶系统的能力。而化合物psi-GSH提供了乙二醛酶系统所需的燃料，来摧毁破坏性的氧化型糖代谢物。在阿尔茨海默氏症模型中，这些氧化型糖代谢物能将正常的脑组织淀粉样蛋白转变成异常形式，导致阿尔茨海默氏症。
在阿尔茨海默氏症易感转基因小鼠中，给药后，psi-GSH减少了大脑中异常β-淀粉样蛋白的堆积。psi-GSH给药11周后，阿尔茨海默氏症易感小鼠中诸如记忆及化学脑健康指示物等认知功能依然保持完好。
例如，在标准的阿尔茨海默氏症迷宫测试中，接受psi-GSH治疗的小鼠保留了完整的记忆，而未处理的小鼠则显着失去了记忆及迷宫适应能力，与晚期阿尔茨海默氏症症状一致。此外，处理过的小鼠没有发现大脑斑块，而未经处理的小鼠呈现显着的斑块积累。
这些研究中，未观察到与psi-GSH相关的大脑及其他重要器官的毒性。（生物谷bioon.com）
编译自：University of Minnesota researchers find new target for Alzheimer's drug development
doi:10.1021/cn3001679
PMC:
PMID:
Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease
Robert Vince , Swati Sudhakar More , and Ashish Pramod Vartak
Abstract：Pathologically high brain levels of reactive dicarbonyls such as methylglyoxal or glyoxal initiate processes that lead ultimately to neurodegeneration, presented clinically as Alzheimer’s disease and other cognitive or motor impairment disorders. Methylglyoxal and glyoxal result from glycolysis and normal metabolic pathways. Their reaction products with proteins (advanced glycation end-products), and their primary chemical toxicities are both linked unequivocally to the primary pathologies of Alzheimer’s disease, viz., amyloid plaques and neurofibrillary tangles. Generation of dicarbonyls is countered through the latter’s reduction by the glutathione-dependent glyoxalase-I enzyme system. Although glyoxalase is overexpressed in early and middle-stages of Alzheimer’s disease, glutathione depletion in the Alzheimer’s-afflicted brain cripples its efficacy. Due to the lack of a suitable pharmacological tool, the restoration of glyoxalase enzyme activity in pre-Alzheimer’s or manifest Alzheimer’s remains yet unvalidated as a means for anti-Alzheimer’s therapy development. Disclosed herein are the results of a preclinical study into the therapeutic efficacy of ψ-GSH, a synthetic cofactor of glyoxalase, in mitigating Alzheimer’s indicators in a transgenic mouse model (APP/PS1) that is predisposed to Alzheimer’s disease. ψ-GSH administration completely averts the development of spatial mnemonic and long-term cognitive/cued-recall impairment. Amyloid β deposition and oxidative stress indicators are drastically reduced in the ψ-GSH treated APP/PS1 mouse. ψ-GSH lacks discernible toxicity at strikingly high doses of 2000 mg/kg. The hypothesis that restoring brain glyoxalase activity would ameliorate neurogeneration stands validated, thus presenting a much needed new target for design of anti-Alzheimer’s therapeutics. Corollarily, ψ-GSH is established as a candidate for drug-development.
