Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease
Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease
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DOI：
10.1021/cn3001679
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发表时间：
2013-02-01
影响因子：
5
通讯作者：
Vince, Robert
中科院分区：
文献类型：
--
作者：
More, Swati S.;Vartak, Ashish P.;Vince, Robert
病理上高水平的反应性二羰基，如甲基乙二醛或乙二醛，启动过程，最终导致神经退化，临床表现为阿尔茨海默病和其他认知或运动障碍障碍。甲基乙二醛和乙二醛是糖酵解和正常代谢途径的产物。它们与蛋白质的反应产物(晚期糖基化终产物)以及它们的主要化学毒性都明确地与阿尔茨海默病的主要病理机制有关，即淀粉样斑块和神经原纤维缠结。依赖谷胱甘肽的乙二醛酶系统通过还原二羰基来对抗二羰基的生成。尽管乙草酸酶-I在阿尔茨海默病的早期和中期过度表达，但阿尔茨海默病患者大脑中谷胱甘肽的枯竭削弱了其疗效。由于缺乏合适的药理学工具，恢复阿尔茨海默病前期或显性阿尔茨海默病患者的乙醛酸酶活性仍未被证实为抗阿尔茨海默病治疗的一种手段。在此公开的是一项临床前研究结果，该研究是关于乙醛酸酶的合成辅因子psi-GSH在减轻易患阿尔茨海默病的转基因小鼠模型(APP/PS1)中的阿尔茨海默氏症指标方面的疗效。给予PSI-GSH完全避免了空间记忆力和长期认知/线索-回忆障碍的发展。在psi-GSH处理的APP/PS1小鼠中，淀粉样β沉积和氧化应激指标显著减少。PSI-GSH在2000 mg/kg的高剂量下没有明显的毒性。恢复大脑乙醛酸酶活性将改善神经生成的假设得到了证实，从而为抗阿尔茨海默氏症疗法的设计提供了一个亟需的新靶点。因此，psi-GSH被确定为药物开发的候选药物。
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, namely, amyloid plaques and neurofibrillary tangles. Generation of dicarbonyls is countered through the reduction of dicarbonyls by the glutathione-dependent glyoxalase enzyme system. Although glyoxalase-I 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 psi-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. psi-GSH administration completely averts the development of spatial mnemonic and long-term cognitive/cued-recall impairment. Amyloid beta deposition and oxidative stress indicators are drastically reduced in the psi-GSH-treated APP/PS1 mouse. psi-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. Consequently, psi-GSH is established as a candidate for drug-development.