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Elevation of mitochondrial glutathione by γ‐glutamylcysteine ethyl ester protects mitochondria against peroxynitrite‐induced oxidative stress
Author(s) -
Drake Jennifer,
Sultana Rukhsana,
Aksenova Marina,
Calabrese Vittorio,
Butterfield D. Allan
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10810
Subject(s) - peroxynitrite , mitochondrion , oxidative stress , glutathione , oxidative phosphorylation , chemistry , biochemistry , microbiology and biotechnology , nitrotyrosine , in vivo , cytochrome c , pharmacology , biology , superoxide , nitric oxide synthase , enzyme
Mitochondria under oxidative stress are thought to play a key role in various neurodegenerative disorders by directing neurons to cell death. Protection by antioxidants against oxidative stress to mitochondria may prove to be beneficial in delaying onset or progression of these diseases. We have investigated the ability of γ‐glutamylcysteine ethyl ester (GCEE) to upregulate mitochondrial glutathione (GSH) in vivo or in vitro and protect against subsequent in vitro peroxynitrite (ONOO−) damage. Mitochondria pretreated in vitro with GCEE were protected against oxidative damage induced by peroxynitrite, as assessed by mitochondrial swelling, changes in mitochondrial membrane potential, 3‐nitrotyrosine formation, protein carbonyl formation, and cytochrome c release. Loss of mitochondrial function in neuronal cell cultures by the oxidants 2,2,′Azobis(2‐amidino‐propane)dihydrochloride (AAPH) and ONOO− was ameliorated by treatment with GCEE. In vivo studies showed that mitochondria isolated from animals injected intraperitoneally with GCEE were protected partially against oxidative modifications induced by ONOO−. Taken together, these results suggest that GCEE may be effective in increasing mitochondrial GSH and may be prove to have therapeutic relevance in neurodegenerative disorders associated with oxidative stress and mitochondrial dysfunction. © 2003 Wiley‐Liss, Inc.