Document Detail


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.
MedLine Citation:
PMID:  15678514     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Debra Boyd-Kimball; Rukhsana Sultana; Hafiz Mohmmad Abdul; D Allan Butterfield
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neuroscience research     Volume:  79     ISSN:  0360-4012     ISO Abbreviation:  J. Neurosci. Res.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-02-22     Completed Date:  2005-05-09     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7600111     Medline TA:  J Neurosci Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  700-6     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2005 Wiley-Liss, Inc.
Affiliation:
Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / drug therapy
Amyloid / ultrastructure
Amyloid beta-Protein / antagonists & inhibitors,  toxicity*
Animals
Cell Count
Cells, Cultured
DNA Fragmentation / drug effects
Dipeptides / pharmacology*,  therapeutic use
Drug Interactions
Embryo, Mammalian
Glutathione / metabolism*
Microscopy, Electron, Transmission / methods
Neurons / drug effects*,  physiology
Neurotoxicity Syndromes / drug therapy
Oxidative Stress / drug effects*,  physiology
Peptide Fragments / antagonists & inhibitors,  toxicity*
Propidium / diagnostic use
Rats
Rats, Sprague-Dawley
Up-Regulation / drug effects*
Grant Support
ID/Acronym/Agency:
AG-05119/AG/NIA NIH HHS; AG-10836/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid; 0/Amyloid beta-Protein; 0/Dipeptides; 0/Peptide Fragments; 0/amyloid beta-protein (1-42); 114627-30-4/N-gamma-glutamylcysteine ethyl ester; 36015-30-2/Propidium; 70-18-8/Glutathione

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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