Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion

Stephen A. Back, Xiaodong Gan, Ya Li, Paul A. Rosenberg, Joseph J. Volpe

Research output: Contribution to journalArticlepeer-review

502 Scopus citations


Death of oligodendrocyte (OL) precursors can be triggered in vitro by cystine deprivation, a form of oxidative stress that involves depletion of intracellular glutathione. We report here that OLs demonstrate maturation- dependent differences in survival when subjected to free radical-mediated injury induced by glutathione depletion. Using immunopanning to isolate rat preoligodendrocytes (preOLs), we generated highly enriched populations of preOLs and mature OLs under chemically defined conditions. Cystine deprivation caused a similar decrease in glutathione levels in OLs at both stages. However, preOLs were completely killed by cystine deprivation, whereas mature OLs remained viable. Although the glutathione-depleting agents buthionine sulfoximine and diethylmaleate were more potent in depleting glutathione in mature OLs, both agents were significantly more toxic to preOLs. Glutathione depletion markedly increased intracellular free radical generation in preOLs, but not in mature OLs, as indicated by oxidation of the redox-sensitive probe dihydrorhodamine 123. The antioxidants α-tocopherol, idebenone, and glutathione monoethylester prevented the oxidation of dihydrorhodamine in cystine-depleted preOLs and markedly protected against cell death. When the intracellular glutathione level was not manipulated, preOLs were also more vulnerable than mature OLs to exogenous free radical toxicity generated by a xanthine-xanthine oxidase system. Ultrastructural features of free radical-mediated injury in glutathione-depleted preOLs included nuclear condensation, margination of chromatin, and mitochondrial swelling. These observations indicate that preOLs are significantly more sensitive to the toxic effects of glutathione depletion and that oligodendroglial maturation is associated with decreased susceptibility to oxidative stress.

Original languageEnglish (US)
Pages (from-to)6241-6253
Number of pages13
JournalJournal of Neuroscience
Issue number16
StatePublished - Aug 15 1998
Externally publishedYes


  • Cystine
  • Free radicals
  • Glutathione
  • Growth factor
  • Oligodendrocyte
  • Oxidative stress

ASJC Scopus subject areas

  • General Neuroscience


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