Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice

Stroke. 2013 Dec;44(12):3516-21. doi: 10.1161/STROKEAHA.113.002813. Epub 2013 Sep 26.


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.

Keywords: mice; oligodendrocyte; reactive oxygen species; white matter diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipyrine / analogs & derivatives
  • Antipyrine / pharmacology
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology*
  • Disease Models, Animal
  • Edaravone
  • Free Radical Scavengers / pharmacology
  • Mice
  • Nerve Fibers, Myelinated / drug effects
  • Nerve Fibers, Myelinated / pathology*
  • Nerve Fibers, Myelinated / physiology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / pathology
  • Neural Stem Cells / physiology*
  • Neurogenesis / physiology*
  • Oligodendroglia / drug effects
  • Oligodendroglia / pathology
  • Oligodendroglia / physiology*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Reactive Oxygen Species / metabolism


  • Free Radical Scavengers
  • Reactive Oxygen Species
  • Edaravone
  • Antipyrine