Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer's Disease.
Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer's Disease.
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DOI：
10.1021/acs.jmedchem.2c00779
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发表时间：
2022-11-10
影响因子：
7.3
通讯作者：
More, Swati S.
中科院分区：
文献类型：
--
作者：
Xie, Wei;Cao, Bin;Zhu, Haizhou;Raza, Abbas;Juckel, Nicholas;Xie, Jiashu;Jiang, Rongrong;Vince, Robert;Lee, Michael K.;More, Swati S.
Addressing glycation-induced oxidative stress in Alzheimer’s disease (AD) is an emerging pharmacotherapeutic strategy. Restoration of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls is one such approach. Toward this end, we designed, synthesized, and evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate, ψ-GSH. Although mechanistically successful, the oral efficacy of ψ-GSH appeared as an area in need of improvement. Herein, we describe our rationale for the creation of prodrugs that mask the labile sulfhydryl group. In vitro and in vivo stability studies identified promising prodrugs that could deliver pharmacologically relevant brain levels of ψ-GSH. When administered orally to a mouse model generated by the intracerebroventricular injection of Aβ1–42, the compounds conferred cognitive benefits. Biochemical and histological examination confirmed their effects on neuroinflammation and oxidative stress. Collectively, we have identified orally efficacious prodrugs of ψ-GSH that are able to restore brain glyoxalase activity and mitigate inflammatory and oxidative pathology associated with AD.
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影响因子：
--
作者：
Hanigan, Marie H.
通讯作者：
Hanigan, Marie H.
DOI：
10.4161/derm.22028
发表时间：
2012-07-01
期刊：
Dermato-endocrinology
影响因子：
--
作者：
Gkogkolou P;Böhm M
通讯作者：
Böhm M
DOI：
10.1016/j.jpba.2006.12.035
发表时间：
2007-04-11
影响因子：
3.4
作者：
Asafu-Adjaye, Ebenezer B.;Faustino, Patrick J.;Volpe, Donna A.
通讯作者：
Volpe, Donna A.
影响因子：
4.7
作者：
Hassel, B;Bråthe, A;Petersen, D
通讯作者：
Petersen, D
影响因子：
4.8
作者：
Kannan, R;Yi, JR;Kaplowitz, N
通讯作者：
Kaplowitz, N