Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice.
OBJECTIVE
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.
From the Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (N.M., T.M., L.-D.D.P., K.H., J.H.S., E.T.M., E.H.L., K.A.); Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA (J.B.M.); and NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences (J.H.S., K.-W.K.) and Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology (K.-W.K.), Seoul National University, Seoul, Korea.
Nobukazu
N
Miyamoto
Takakuni
T
Maki
Loc-Duyen D
LD
Pham
Kazuhide
K
Hayakawa
Ji Hae
JH
Seo
Emiri T
ET
Mandeville
Joseph B
JB
Mandeville
Kyu-Won
KW
Kim
Eng H
EH
Lo
Ken
K
Arai
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D000077553:Edaravone; D000983:Antipyrine
mice; oligodendrocyte; reactive oxygen species; white matter diseases