Protective effect of new S-acylglutathione derivatives against amyloid-induced oxidative stress.
Recent data support the role of oxidative stress in the pathogenesis of Alzheimer disease (AD). In particular, glutathione (GSH) metabolism is altered and its levels are decreased in affected brain regions and peripheral cells from AD patients and in experimental models of AD. In the past decade, interest in the protective effects of various antioxidants aimed at increasing intracellular GSH content has been growing. Because much experimental evidence suggests a possible protective role of unsaturated fatty acids in age-related diseases, we designed the synthesis of new S-acylglutathione (acyl-SG) thioesters. S-Lauroylglutathione (lauroyl-SG) and S-palmitoleoylglutathione (palmitoleoyl-SG) were easily internalized into the cells and they significantly reduced Abeta42-induced oxidative stress in human neurotypic SH-SY5Y cells. In particular, acyl-SG thioesters can prevent the impairment of intracellular ROS scavengers, intracellular ROS accumulation, lipid peroxidation, and apoptotic pathway activation. Palmitoleoyl-SG seemed more effective in cellular protection against Abeta-induced oxidative damage than lauroyl-SG, suggesting a valuable role for the monounsaturated fatty acid. In this study, we demonstrate that acyl-SG derivatives completely avoid the sharp lipoperoxidation in primary fibroblasts from familial AD patients occurring after exposure to Abeta42 aggregates. Hence, we put forward these derivatives as new antioxidant compounds which could be excellent candidates for therapeutic treatment of AD and other oxidative stress-related diseases.
Pensalfini
Anna
A
Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy.
Cecchi
Cristina
C
Zampagni
Mariagioia
M
Becatti
Matteo
M
Favilli
Fabio
F
Paoli
Paolo
P
Catarzi
Serena
S
Bagnoli
Silvia
S
Nacmias
Benedetta
B
Sorbi
Sandro
S
Liguri
Gianfranco
G
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects*; D005978:Glutathione / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007848:Laurates / Q000138:chemical synthesis / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D010168:Palmitates / Q000138:chemical synthesis / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D007848:Laurates; D010168:Palmitates; D017382:Reactive Oxygen Species; C529551:S-lauroylglutathione; C529552:S-palmitoleoylglutathione; D005978:Glutathione