EXACERBATION OF CEREBRAL INJURY IN MICE THAT EXPRESS THE P-SELECTIN GENE - IDENTIFICATION OF P-SELECTIN BLOCKADE AS A NEW TARGET FOR THE TREATMENT OF STROKE

There is currently a stark therapeutic void in the treatment of evolvi ng stroke. Although P-selectin is rapidly expressed by hypoxic endothe lial cells in vitro, the functional significance of P-selectin express ion in stroke remains unexplored. In order to identify the pathophysio logical consequences of P-selectin expression and to identify P-select in blockade as a potential new approach for the treatment of stroke, e xperiments were performed using a murine model of focal cerebral ische mia and reperfusion. Early P-selectin expression in the postischemic c erebral cortex was demonstrated by the specific accumulation of radiol abeled anti-murine P-selectin IgG, with the increased P-selectin expre ssion localized to the ipsilateral cerebral microvascular endothelial cells by immunohistochemistry. In experiments designed to test the fun ctional significance of increased P-selectin expression in stroke, neu trophil accumulation in the ischemic cortex of mice expressing the P-s electin gene (PS +/+) was demonstrated to be significantly greater tha n that in homozygous P-selectin-null mice (PS -/-). Reduced neutrophil influx was accompanied by greater postischemic cerebral reflow (measu red by laser Doppler) in the PS -/- mice. In addition, PS -/- mice dem onstrated smaller infarct volumes (5-fold reduction, P<.05) and improv ed survival compared with PS +/+ mice (88% versus 44%, P<.05). Functio nal blockade of P-selectin in PS +/+ mice using a monoclonal antibody directed against murine P-selectin also improved early reflow and stro ke outcome compared with control mice, with reduced cerebral infarctio n volumes noted even when the blocking antibody was administered after occlusion of the middle cerebral artery. These data are the first to demonstrate a pathophysiological role for P-selectin in stroke and sug gest that P-selectin blockade may represent a new therapeutic target i n the treatment of stroke.