Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1-42)-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease.
Glutathione (GSH) is an important endogenous antioxidant found in millimolar concentrations in the brain. GSH levels have been shown to decrease with aging. Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging and oxidative stress. Abeta(1-42) has been shown to induce oxidative stress and has been proposed to play a central role in the oxidative damage detected in AD brain. It has been shown that administration of gamma-glutamylcysteine ethyl ester (GCEE) increases cellular levels of GSH, circumventing the regulation of GSH biosynthesis by providing the limiting substrate. In this study, we evaluated the protective role of up-regulation of GSH by GCEE against the oxidative and neurotoxic effects of Abeta(1-42) in primary neuronal culture. Addition of GCEE to neurons led to an elevated mean cellular GSH level compared with untreated control. Inhibition of gamma-glutamylcysteine synthetase by buthionine sulfoximine (BSO) led to a 98% decrease in total cellular GSH compared with control, which was returned to control levels by addition of GCEE. Taken together, these results suggest that GCEE up-regulates cellular GSH levels which, in turn, protects neurons against protein oxidation, loss of mitochondrial function, and DNA fragmentation induced by Abeta(1-42). These results are consistent with the notion that up-regulation of GSH by GCEE may play a viable protective role in the oxidative and neurotoxicity induced by Abeta(1-42) in AD brain.
Boyd-Kimball
Debra
D
Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
Sultana
Rukhsana
R
Abdul
Hafiz Mohmmad
HM
Butterfield
D Allan
DA
D000544:Alzheimer Disease / Q000188:drug therapy; D000682:Amyloid / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005978:Glutathione / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000188:drug therapy; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D004151:Dipeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C067744:N-gamma-glutamylcysteine ethyl ester; D011419:Propidium; D005978:Glutathione