Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 30, Issue 5, Pages 1044-1052Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2009.283
Keywords
platelet/endothelial interactions; protease-activated receptor 4; brain ischemia; inflammation; blood-brain barrier
Categories
Funding
- National Institutes of Health [HL81322, HL80444, HL60683, DA P30 13429, DA 03672, DA 05488]
- Pennsylvania Department of Health
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Stroke is the third leading cause of death in the USA. Antithrombotic therapy targeting platelet activation is one of the treatments for ischemic stroke. Here we investigate the role of one of the thrombin receptors, protease-activated receptor 4 (PAR4), in a mouse transient middle cerebral artery occlusion (MCAO) model. After a 60 min MCAO and 23 h reperfusion, leukocyte and platelet rolling and adhesion on cerebral venules, blood-brain barrier (BBB) permeability, and cerebral edema were compared in PAR4-deficient mice and wild-type mice. Cerebral infarction volume and neuronal death were also measured. PAR4(-/-) mice had more than an 80% reduction of infarct volume and significantly improved neurologic and motor function compared with wild-type mice after MCAO. Furthermore, deficiency of PAR4 significantly inhibits the rolling and adhesion of both platelets and leukocytes after MCAO. BBB disruption and cerebral edema were also attenuated in PAR4(-/-) mice compared with wild-type animals. The results of this investigation indicate that deficiency of PAR4 protects mice from cerebral ischemia/reperfusion (I/R) injury, partially through inhibition of platelet activation and attenuation of microvascular inflammation. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1044-1052; doi: 10.1038/jcbfm.2009.283; published online 20 January 2010
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