Published Online
on April 8, 2004

A more recent version of this article appeared on June 1, 2004

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Submitted on July 2, 2003
Accepted on February 2, 2004

Reperfusion-Induced Oxidative/Nitrative Injury to Neurovascular Unit after Focal Cerebral Ischemia

Yasemin Gürsoy-Özdemir MD, PhD; Alp Can MD; and Turgay Dalkara MD, PhD^*

From the Department of Neurology (Y.G.-Ö., T.D.), Faculty of Medicine, and Institute of Neurological Sciences & Psychiatry, Hacettepe University, Ankara, Turkey; and Department of Histology-Embryology (A.C.), Ankara University School of Medicine, Ankara, Turkey.

^* To whom correspondence should be addressed. E-mail: tdalkara{at}hacettepe.edu.tr.

Background and Purpose--Use of thrombolysis in stroke is limited by a short therapeutic window because delayed reperfusion may cause brain hemorrhage and edema. Available evidence suggests a role for superoxide, NO, and peroxynitrite in reperfusion-induced injury. However, depending on their cellular origin and interactions between them, these molecules may exert protective or deleterious actions, neither of which is characterized in the intact brain.

Methods--Using fluorescent probes, we determined superoxide and peroxynitrite formation within neurons, astrocytes, and endothelium, and the association between oxidative/nitrative stress and vascular injury in mice brains subjected to 2-hour middle cerebral artery occlusion and 3 or 5 hours of reperfusion.

Results--Both signals were colocalized, suggesting that the main source of peroxynitrite in the reperfused brain was a reaction between superoxide and NO. Superoxide and peroxynitrite formation was particularly intense in microvessels and astrocytic end-feet surrounding them, and overlapped with dense mitochondrial labeling. Sites of oxidative/nitrative stress on microvessels were colocalized with markers of vascular injury such as Evans blue (EB) leakage and matrix metalloproteinase-9 (MMP-9) expression, suggesting an association between peroxynitrite and microvascular injury. Supporting this idea, partial inhibition of endothelial NO synthesis at reperfusion with a low dose of L-nitroarginine (1 mg/kg IP) reduced 3-nitrotyrosine formation in microvessels and EB extravasation.

Conclusion--During reperfusion, intense superoxide, NO, and peroxynitrite formation on microvessels and surrounding end-feet may lead to cerebral hemorrhage and edema by disrupting microvascular integrity. Combination of thrombolysis with agents diminishing oxidative/nitrative stress may reduce reperfusion-induced injury and extend the therapeutic window for thrombolysis.

Key words: blood-brain barrier • matrix metalloproteinases • nitric oxide • peroxynitrite • reactive oxygen species • reperfusion injury • thrombolysis

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