Inhibition of neutrophil migration by a protein kinase inhibitor for the treatment of ischemic brain infarction

This study investigated the therapeutic potential of agents that inhibited neutrophil infiltration in cerebral ischemic infarction. The migration of n eutrophils elicited by N-formyl-methionyl-leucylphenylalanine, tumor necros is factor, C5a or platelet-activating factor was potently inhibited by fasu dil, an inhibitor of protein kinases including rho kinase, protein kinase C and myosin light chain kinase, and hydroxy fasudil, a metabolite of fasudi l, in vitro. In a microembolism model in rats, myeloperoxidase-quantified n eutrophil accumulation in the ischemic brain was observed 24 hr after embol ization. Intravenous administration of fasudil prevented the accumulation o f neutrophils. In rats given fasudil, myeloperoxidase activity in the ipsil ateral hemisphere (0.04+/-0.01 unit/g wet tissue) was significantly lower t han that in ischemic rats (0.11+/-0.02 unit/g wet tissue). Fasudil also sig nificantly reduced the size of the infarct area and improved neurological f unctions. These results suggest that neutrophil infiltration into the ische mic brain is involved in the pathogenesis of ischemic injury and that inhib iting neutrophil infiltration may provide an effective therapeutic interven tion to reduce ischemic injury.