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

被引：54

作者：

Zampagni, Mariagioia ^{[1
]}

Wright, Daniel ^{[1
]}

Cascella, Roberta ^{[1
]}

D'Adamio, Giampiero ^{[2
]}

Casamenti, Fiorella ^{[3
]}

Evangelisti, Elisa ^{[1
]}

Cardona, Francesca ^{[2
]}

Goti, Andrea ^{[2
]}

Nacmias, Benedetta ^{[4
]}

Sorbi, Sandro ^{[4
]}

Liguri, Gianfranco ^{[1
]}

Cecchi, Cristina ^{[1
]}

机构：

[1] Univ Florence, Dept Biochem Sci, I-50134 Florence, Italy

[2] Univ Florence, Dept Chem Ugo Schiff, I-50019 Florence, Italy

[3] Univ Florence, Dept Pharmacol, I-50139 Florence, Italy

[4] Univ Florence, Dept Neurol & Psychiat Sci, I-50139 Florence, Italy

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2012年 / 52卷 / 08期

关键词：

Thioester chemical synthesis; S-acyl glutathione derivatives; Familial Alzheimer fibroblasts; Cholinergic neurons; Oxidative stress; Antioxidants; A beta 42 toxicity; Polyunsaturated fatty acids; Free radicals; DOCOSAHEXAENOIC ACID; IN-VIVO; BRAIN; NEURODEGENERATION; PATHOGENESIS; INFLAMMATION; CHOLESTEROL; INVOLVEMENT; MECHANISMS; HYPOTHESIS;

D O I：

10.1016/j.freeradbiomed.2012.01.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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 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. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：1362 / 1371

页数：10