In vivo modulation of rodent glutathione and its role in peroxynitrite-induced neocortical synaptosomal membrane protein damage

Tanuja Koppal, Jennifer Drake, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Peroxynitrite, formed by the reaction between nitric oxide and superoxide, leads to the oxidation of proteins, lipids, and DNA, and nitrates thiols such as cysteine and glutathione, and amino acids like tyrosine. Previous in vitro studies have shown glutathione to be an efficient scavenger of peroxynitrite, protecting synaptosomal membranes from protein oxidation, the enzyme glutamine synthetase from inactivation, and preventing the death of hippocampal neurons in culture. The current study was undertaken to see if in vivo modulation of glutathione levels would affect brain cortical synaptosomal membrane proteins and their subsequent reaction with peroxynitrite. Glutathione levels were depleted, in vivo, by injecting animals with 2-cyclohexen-1-one (CHX, 100 mg/kg body weight), and levels of glutathione were enhanced by injecting animals with N-acetylcysteine (NAC, 200 mg/kg body weight), which gets metabolized to cysteine, a precursor of glutathione. Changes in membrane protein conformation and structure in synaptosomes subsequently isolated from these animals were examined using electron paramagnetic resonance, before and after in vitro addition of peroxynitrite. The animals injected with the glutathione depletant CHX showed greater damage to the membrane proteins both before and after peroxynitrite treatment, compared to the non-injected controls. The membrane proteins from animals injected with NAC were comparable to controls before peroxynitrite treatment and were partially protected against peroxynitrite-induced damage. This study showed that modulation of endogenous glutathione levels can affect the degree of peroxynitrite-induced brain membrane damage and may have potential therapeutic significance for oxidative stress-associated neurodegenerative disorders. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)407-411
Number of pages5
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1453
Issue number3
DOIs
StatePublished - Mar 30 1999

Bibliographical note

Funding Information:
This work was supported in part by grants from NIH (AG-05119, AG-10836). We are grateful to Dr. Dibakar Bhattacharyya, Department of Chemical and Materials Engineering, University of Kentucky, for the use of his ozonator for the synthesis of peroxynitrite.

Keywords

  • Glutathione
  • N-Acetylcysteine
  • Oxidative stress
  • Peroxynitrite

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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