Delayed treatment of experimental ischemic stroke with a bradykinin B2 receptor antagonist

Inflammatory responses have been implicated in the biological events that begin with the occlusion of one large cerebral artery and that eventually lead to the development of a brain infarction. Bradykinin, an important mediator of the inflammatory response, requires the interaction with the B-2, receptor (constitutive). Wistar rats treated with a B2 receptor antagonist, CP-0597, at the time one MCA was occluded significantly benefited when compared to control rats, in experiments terminated 24 h after a transient (60 min) MCA occlusion (MCA-O). In these experiments we examined the question whether the treatment with CP-0597 would be effective if it started 1-2 h after MCA-O, whether the effects would be equally beneficial in cases of either permanent or transient arterial occlusion, and whether the benefits would be demonstrable seven days after the arterial occlusion. Forty-six Wistar rats were divided into groups that had either permanent or transient (60 min) MCA occlusion. All experiments were terminated after seven days. Control groups had sham operations and the endpoints in the groups treated with the B2 receptor antagonist (CP-0597) were compared against those treated with placebo. Endpoints included: changes in body weight, motorsensory score, WBC count in venous blood, surface area of the brain lesion, and analysis of the type of brain lesion induced by the arterial occlusion. In the group with permanent MCA-O there were significant differences between the treatment (TG) and placebo (PG) subgroups: there were two premature deaths in PG, none in TG; persistent drop in the WBC in the TG compared to the PG (p = <0.05), and smaller surface area in the cortical lesion of the TG (40.2%) versus the PG (67%), (p = <0.05). Meaningful analysis of the results in the groups with transient MCA-O were made difficult by the fact that the heterogeneity of the brain lesions produced by a transient arterial occlusion resulted in 3-4 subgroups each having only 2 or 3 subjects. In summary: Treatment of experimental ischemic stroke with CP-0597 confers benefits, detectable seven days later, even when the compound is administered one hour after MCA-O and the artery remains occluded. The drug effect includes persistent leukopenia and treatment benefits may be mediated by a significant decrease in post-ischemic brain swelling. Establishing the potential beneficial effects of treatment with CP-0597 in experiments involving transient MCA-O requires additional experiments involving larger samples.