title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Boyd-Kimball
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Hafiz Mohmmad
authors.initials: HM
authors.lastname: Abdul
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: 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*
chemical_list: 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