Oxidative Stress Interferes With White Matter Renewal After Prolonged Cerebral Hypoperfusion in Mice

And they talk about edaravone (approved for use in Japan since 2001).
Is your doctor working to get this approved in the US?
http://stroke.ahajournals.org/content/44/12/3516.abstract?etoc

1. Nobukazu Miyamoto, MD, PhD;
2. Takakuni Maki, MD, PhD;
3. Loc-Duyen D. Pham, MS;
4. Kazuhide Hayakawa, PhD;
5. Ji Hae Seo, PhD;
6. Emiri T. Mandeville, MD, PhD;
7. Joseph B. Mandeville, PhD;
8. Kyu-Won Kim, PhD;
9. Eng H. Lo, PhD;
10. Ken Arai, PhD

+ Author Affiliations

1. 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.

1. 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.