Novel S-acyl glutathione derivatives prevent amyloid oxidative stress and cholinergic dysfunction in Alzheimer disease models

作者：Zampagni Mariagioia; Wright Daniel; Cascella Roberta; D' Adamio Giampiero; Casamenti Fiorella; Evangelisti Elisa; Cardona Francesca; Goti Andrea; Nacmias Benedetta; Sorbi Sandro; Liguri Gianfranco; Cecchi Cristina^*

来源：Free Radical Biology and Medicine, 2012, 52(8): 1362-1371.

DOI：10.1016/j.freeradbiomed.2012.01.012

• Thioester chemical synthesis
• S-acyl glutathione derivatives
• Familial Alzheimer fibroblasts
• Cholinergic neurons
• Oxidative stress
• Antioxidants
• A beta 42 toxicity
• Polyunsaturated fatty acids
• Free radicals

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 beta-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.

• 出版日期2012-4-15