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The Journal of Neuroscience, August 15, 1998, 18(16):6241-6253
Maturation-Dependent Vulnerability of Oligodendrocytes to
Oxidative Stress-Induced Death Caused by Glutathione Depletion
Stephen A.
Back,
Xiaodong
Gan,
Ya
Li,
Paul A.
Rosenberg, and
Joseph J.
Volpe
Department of Neurology, Children's Hospital and Harvard Medical
School, Boston, Massachusetts 02115
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 -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.
Key words:
oligodendrocyte; glutathione; cystine; free radicals; oxidative stress; growth factor
Copyright © 1998 Society for Neuroscience 0270-6474/98/18166241-13$05.00/0
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