Substance P (SP) has been implicated in immune responses and could increase glutamate release, and inflammatory reactions are known to be able to potentiate ischemic damage. We have previously found that SP was over-expressed in cerebral ischemia and speculated that SP may play a role in exacerbating ischemic damage. In this study, we examined whether a neurokinin-1 (NK-1) receptor antagonist, SR140333, would have an effect on brain ischemia. Intra-cerebroventricular (i.c.v.) administration of SR140333 (30 micrograms) markedly reduced (37.1 +/- 7.8%, p < 0.001) infarct volume measured 24 h after focal cerebral ischemia in the rat. The SR140333-treated group also exhibited a significantly improved neurological function reflected by the neurological deficit score. The results represented the first demonstration that a NK-1 receptor antagonist may be a novel type of drug for treatment of cerebral ischemia.