γ-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Aβ(1-42)-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

Debra Boyd-Kimball, Rukhsana Sultana, Hafiz Mohmmad Abdul, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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. Aβ(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 γ-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 Aβ(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 γ-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 Aβ(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 Aβ(1-42) in AD brain.

Original languageEnglish
Pages (from-to)700-706
Number of pages7
JournalJournal of Neuroscience Research
Volume79
Issue number5
DOIs
StatePublished - Mar 1 2005

Keywords

  • Alzheimer's disease
  • Amyloid beta peptide
  • Glutathione

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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