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http://stroke.ahajournals.org/content/44/12/3516.abstract?etoc
- Nobukazu Miyamoto, MD, PhD;
- Takakuni Maki, MD, PhD;
- Loc-Duyen D. Pham, MS;
- Kazuhide Hayakawa, PhD;
- Ji Hae Seo, PhD;
- Emiri T. Mandeville, MD, PhD;
- Joseph B. Mandeville, PhD;
- Kyu-Won Kim, PhD;
- Eng H. Lo, PhD;
- Ken Arai, PhD
+ Author Affiliations
- Correspondence to Ken Arai, PhD, Neuroprotection Research Laboratory, Massachusetts General Hospital, E 149-2401, Charlestown, MA 02129. E-mail karai@partners.org
Abstract
Background and Purpose—White
matter injury caused by cerebral hypoperfusion may contribute to the
pathophysiology of vascular dementia and stroke,
but the underlying mechanisms remain to be
fully defined. Here, we test the hypothesis that oxidative stress
interferes with
endogenous white matter repair by disrupting
renewal processes mediated by oligodendrocyte precursor cells (OPCs).
Methods—In vitro, primary rat OPCs were exposed to sublethal CoCl2
for 7 days to induce prolonged chemical hypoxic stress. Then, OPC
proliferation/differentiation was assessed. In vivo, prolonged
cerebral hypoperfusion was induced by
bilateral common carotid artery stenosis in mice. Then, reactive oxygen
species production,
myelin density, oligodendrocyte versus OPC
counts, and cognitive function were evaluated. To block oxidative
stress, OPCs
and mice were treated with the radical
scavenger edaravone.
Results—Prolonged
chemical hypoxic stress suppressed OPC differentiation in vitro. Radical
scavenging with edaravone ameliorated these
effects. After 28 days of cerebral
hypoperfusion in vivo, reactive oxygen species levels were increased in
damaged white matter,
along with the suppression of
OPC-to-oligodendrocyte differentiation and loss of myelin staining.
Concomitantly, mice showed
functional deficits in working memory.
Radical scavenging with edaravone rescued OPC differentiation,
ameliorated myelin loss,
and restored working memory function.
Conclusions—Our
proof-of-concept study demonstrates that after prolonged cerebral
hypoperfusion, oxidative stress interferes with white
matter repair by disrupting OPC renewal
mechanisms. Radical scavengers may provide a potential therapeutic
approach for white
matter injury in vascular dementia and
stroke.
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