Novel S-acyl glutathione derivatives prevent amyloid oxidative stress and cholinergic dysfunction in Alzheimer disease models
- 作者：Mariagioia Zampagni<sup>asup> ; Daniel Wright<sup>asup> ; Roberta Cascella<sup>asup> ; Giampiero D'Adamio<sup>bsup> ; Fiorella Casamenti<sup>csup> ; Elisa Evangelisti<sup>asup> ; Francesca Cardona<sup>bsup> ; Andrea Goti<sup>bsup> ; Benedetta Nacmias<sup>dsup> ; Sandro Sorbi<sup>dsup> ; Gianfranco Liguri<sup>asup><sup> ; sup><sup>1sup> ; Cristina Cecchi<sup>asup><sup> ; sup><sup>1sup><sup> ; sup><sup>cristina.cecchi@unifi.itsup>
- 关键词：acyl-SG ; S-acyl glutathione ; AD ; Alzheimer disease ; APP ; amyloid precursor protein ; A尾 ; amyloid-尾 peptide ; BODIPY ; 4 ; 4-difluoro-3a ; 4a-diaza-s-indacene ; ChAT ; choline acetyltransferase ; CM-H2DCFDA ; 2&prime ; 7&prime ; -dichlorodihydrofluorescein diacetate
- 刊名：Free Radical Biology and Medicine
- 出版年：2012
- 期刊代码：105_08915849
- 类别：med
- 出版时间：15 April, 2012
- 卷：52
- 期：8
- 页码：1362-1371
- 文件大小：1988 K
摘要
Oxidative stress-mediated neuronal death may be initiated by a decrease in glutathione (GSH), whose levels are reduced in mitochondrial and synaptosomal fractions of specific CNS regions in Alzheimer disease (AD) patients. Currently, the use of GSH as a therapeutic agent is limited by its unfavorable pharmacokinetic properties. In this study, we designed the synthesis of new S-acyl glutathione (acyl-SG) thioesters of fatty acids via N-acyl benzotriazole-intermediate production and investigated their potential for targeted delivery of the parent GSH and free fatty acid to amyloid-exposed fibroblasts from familial AD patients and human SH-SY5Y neuroblastoma cells. Cell culture supplementation with acyl-SG derivatives triggers a significant decrease in lipid peroxidation and mitochondrial dysfunction in a fatty acid unsaturation degree-dependent fashion. Acyl-SG thioesters also protect cholinergic neurons against A尾-induced damage and reduce glial reaction in rat brains. Collectively, these findings suggest that acyl-SG thioesters could prove useful as a tool for controlling AD-induced cerebral deterioration.