A substance P antagonist improves outcome following reversible middle cerebral artery occlusion in rats

Abstract

Previous results from our laboratory 1 have shown that neurogenic inflammation is associated with traumatic brain injury. This neurogenic inflammation was characterized by increased substance P (SP) immunoreactivity, and could be attenuated with administration of SP antagonists with a resultant decrease in functional deficits. The present study examines SP immunoreactivity following experimental stroke in rats and characterizes the effects of a substance P antagonist on functional outcome. Experimental stroke was induced in halothane anesthetized Sprague-Dawley rats using a reversible thread model of right middle cerebral artery occlusion 2 where occlusion was maintained for 2 h and the thread retracted to allow reperfusion. Animals not exhibiting anti-clockwise circling behaviour at 2 h after commencement of reperfusion were excluded from the study. In a subgroup of animals, either 25 mg/kg n-acetyl-tryptophan or equal volume saline was administered i.v. at this timepoint, and their motor function subsequently assessed for 7 days using a rotarod device. Untreated animals were reanesthetized at 24 h and their brains perfusion fixed with 10% formalin, removed and blocked in paraffin wax. Increased SP immunoreactivity relative to the contralateral (non-infarcted) hemisphere was observed in perivascular, neuronal and glial tissue within the penumbra of the infarcted hemisphere. This increased SP immunoreactivity was not as apparent in the infarct core. In animals receiving treatment, administration of the SP antagonist resulted in a significant improvement in rotarod score as compared to vehicle treated animals. We conclude that neurogenic inflammation, as reflected by increased SP immunoreactivity, occurs in the ischemic penumbra following experimental stroke, and that it may be associated with the development of functional deficits. As such, inhibition of neurogenic inflammation may represent a novel therapeutic target for the treatment of reversible, ischemic stroke (See Figure 1).