CORTICAL PROTECTION BY LOCALIZED STRIATAL INJECTION OF IL-1RA FOLLOWING CEREBRAL-ISCHEMIA IN THE RAT

Interleukin-1 (IL-1) receptor antagonist (IL-1ra) markedly reduces inf arct volume induced by middle cerebral artery occlusion (MCAO) in the rat, when injected either centrally (intracerebroventricularly) or per ipherally. The site or sites of action of IL-I in stroke pathology, ho wever, are not known. The present study investigated the site(s) of ac tion of IL-1/IL-1ra in ischemic brain damage by studying the effects o f local injection of IL-1ra into the cortex or striatum following perm anent MCAO in the rat. Cortical injection of IL-1ra (5 mu g) did not a ffect infarct volume in the cortex or striatum measured 24 h after MCA O. In contrast, striatal injection of IL-1ra ipsilateral to the infarc tion caused a significant and highly reproducible reduction of cortica l (37%, p < 0.001) and striatal damage (27%, p < 0.001, corrected for edema) compared with vehicle-injected animals. Injection of IL-1ra (5 mu g) into the striatum, contralateral to the infarction, resulted in a small (9%) but significant (p < 0.001) reduction of ipsilateral cort ical damage, with no effect on ipsilateral striatal damage. Injection of a higher dose of IL-1ra (7.5 mu g) in the contralateral striatum ca used a further inhibition of ipsilateral cortical damage (24%, p < 0.0 01) and a significant reduction of ipsilateral striatal damage (16%, p < 0.001). In separate groups of rats, it was established that core te mperature (measured continuously in free-moving animals with remote ra diotelemetry) was not affected by striatal or cortical injection of IL -1ra. These data show that injection of IL-1ra into the striatum but n ot the cortex reduces infarct volume in both the striatum and the cort ex, independently of effects on core temperature. These results imply that blocking striatal IL-1 contributes to IL-1ra-protective effects. We hypothesize that IL-1 may influence striatal distal cortical damage through either the release of specific substances or activation of po lysynaptic pathways.