Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke

Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain follow ing stroke and that suppression of Src activity decreases VP thereby minimi zing brain injury. Mice lacking pp60(c-sr)c are resistant to VEGF-induced V P and show decreased infarct volumes after stroke whereas mice deficient in pp59(c-fyn), another Src family member, have normal VEGF-mediated VP and i nfarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-indu ced brain damage without influencing VEGF expression. This was associated w ith reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histol ogical analysis. Thus, Src represents a key intermediate and novel therapeu tic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.