Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer's Disease Mouse Model.
Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer's Disease Mouse Model.
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DOI：
10.3390/antiox11061075
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发表时间：
2022-05-28
期刊：
影响因子：
7
通讯作者：
More, Swati S.
中科院分区：
文献类型：
--
作者：
Raza, Abbas;Xie, Wei;Kim, Kwan-Hyun;Dronamraju, Venkateshwara Rao;Williams, Jessica;Vince, Robert;More, Swati S.
通过不同的配方或前体补充谷胱甘肽（GSH）水平迄今为止似乎是一个可行的策略，以改善疾病相关的氧化应激。GSH及其前体的代谢倾向，即，普遍存在的γ-谷氨酰转肽酶（γ-GT）的水解，由于生物利用度差而限制了成功的临床转化。我们通过设计抗γ-GT的GSH类似物来解决这个问题，其成功地在GSH依赖的酶系统中取代，并且也提供了作为阿尔茨海默病（AD）的治疗剂的前景。为了提高其生物利用度，我们研究了β-GSH前体二肽2作为潜在的AD治疗剂的效用。化合物2保留了γ-GT稳定的酰脲键和硫醇基团以用于抗氧化性质。通过与谷胱甘肽合成酶结合，化合物2能够在体内产生β-GSH。发现它是谷胱甘肽过氧化物酶的一种适度辅因子，并在体外阻止Aβ1-42-聚集体的细胞毒性。化合物2在脑室内注射Aβ1-42产生的急性AD模型中的研究显示出认知益处，其与甘氨酸的组合沿着氧化应激和炎症病理学的减轻而增强。总的来说，这些结果支持进一步优化和评估β-GSH二肽作为转基因AD模型中的潜在治疗剂。
Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical translation due to poor bioavailability. We addressed this problem through the design of γ-GT-resistant GSH analogue, ψ-GSH, which successfully substituted in GSH-dependent enzymatic systems and also offered promise as a therapeutic for Alzheimer’s disease (AD). With the aim to improve its bioavailability, we studied the utility of a ψ-GSH precursor, dipeptide 2, as a potential AD therapeutic. Compound 2 retains the γ-GT stable ureide linkage and the thiol group for antioxidant property. By engaging glutathione synthetase, compound 2 was able to generate ψ-GSH in vivo. It was found to be a modest cofactor of glutathione peroxidase and prevented cytotoxicity of Aβ1–42-aggregates in vitro. Studies of compound 2 in an acute AD model generated by intracerebroventricular injection of Aβ1–42 showed cognitive benefits, which were augmented by its combination with glycine along with mitigation of oxidative stress and inflammatory pathology. Collectively, these results support further optimization and evaluation of ψ-GSH dipeptide as a potential therapeutic in transgenic AD models.
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影响因子：
3.5
作者：
Kawai, Nobuhiro;Bannai, Makoto;Shimizu, Eiji
通讯作者：
Shimizu, Eiji
影响因子：
--
作者：
Hanigan, Marie H.
通讯作者：
Hanigan, Marie H.
影响因子：
5
作者：
More, Swati S.;Vartak, Ashish P.;Vince, Robert
通讯作者：
Vince, Robert
影响因子：
2.2
作者：
Galasko D;Montine TJ
通讯作者：
Montine TJ
DOI：
10.1038/s41573-021-00233-1
发表时间：
2021-09
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Forman HJ;Zhang H
通讯作者：
Zhang H