2012年12月4日訊 /生物谷BIOON/ --明尼蘇達(dá)大學(xué)藥物設(shè)計(jì)中心的研究人員，開發(fā)出了一種人工合成化合物,，該化合物在小鼠模型中，成功阻止了與阿爾茨海默氏癥（Alzheimer's disease,，AD）相關(guān)的神經(jīng)退行性病變（neurodegeneration）,，為阿爾茨海默氏癥及相關(guān)疾病的藥物設(shè)計(jì)指明了一個新靶標(biāo)。
在臨床前研究中,，研究人員發(fā)現(xiàn),，一種名為psi-GSH的實(shí)驗(yàn)室合成化合物，使大腦能夠利用自身的保護(hù)酶系統(tǒng)——乙二醛酶（glyoxalase）阻止阿爾茨海默氏癥疾病進(jìn)程。研究結(jié)果已在線發(fā)表于ACS Chemical Neuroscience期刊,。
“盡管大多數(shù)在研及已上市藥物試圖減緩或逆轉(zhuǎn)阿爾茨海默氏癥的進(jìn)程,，我們的方法卻使大腦能夠利用自身的酶系統(tǒng)在極早期階段抗擊疾病，”藥物設(shè)計(jì)中心主任Vince說道,。
此前科學(xué)家已發(fā)現(xiàn),，阿爾茨海默氏癥能損害大腦利用乙二醛酶系統(tǒng)的能力。而化合物psi-GSH提供了乙二醛酶系統(tǒng)所需的燃料,，來摧毀破壞性的氧化型糖代謝物,。在阿爾茨海默氏癥模型中，這些氧化型糖代謝物能將正常的腦組織淀粉樣蛋白轉(zhuǎn)變成異常形式,，導(dǎo)致阿爾茨海默氏癥,。
在阿爾茨海默氏癥易感轉(zhuǎn)基因小鼠中，給藥后,，psi-GSH減少了大腦中異常β-淀粉樣蛋白的堆積,。psi-GSH給藥11周后，阿爾茨海默氏癥易感小鼠中諸如記憶及化學(xué)腦健康指示物等認(rèn)知功能依然保持完好,。
例如,，在標(biāo)準(zhǔn)的阿爾茨海默氏癥迷宮測試中，接受psi-GSH治療的小鼠保留了完整的記憶,，而未處理的小鼠則顯著失去了記憶及迷宮適應(yīng)能力,，與晚期阿爾茨海默氏癥癥狀一致。此外,，處理過的小鼠沒有發(fā)現(xiàn)大腦斑塊,，而未經(jīng)處理的小鼠呈現(xiàn)顯著的斑塊積累。
這些研究中,，未觀察到與psi-GSH相關(guān)的大腦及其他重要器官的毒性,。（生物谷bioon.com）
編譯自：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.
