Novel S-acyl glutathione derivatives prevent amyloid oxidative stress and cholinergic dysfunction in Alzheimer disease models.
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 Aβ-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.
Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy.
Mariagioia
M
Zampagni
Daniel
D
Wright
Roberta
R
Cascella
Giampiero
G
D'Adamio
Fiorella
F
Casamenti
Elisa
E
Evangelisti
Francesca
F
Cardona
Andrea
A
Goti
Benedetta
B
Nacmias
Sandro
S
Sorbi
Gianfranco
G
Liguri
Cristina
C
Cecchi
D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011950:Receptors, Cholinergic / Q000378:metabolism*
D000682:Amyloid; D011950:Receptors, Cholinergic; D053148:Caspase 3; D005978:Glutathione