Delayed systemic administration of PACAP38 is neuroprotective in transientmiddle cerebral artery occlusion in the rat

Background and Purpose-Many substances have been shown to reduce brain dama ge in models of stroke, but mainly when given either before or shortly afte r the onset of ischemia. Delayed systemic administration of pituitary adeny late cyclase-activating polypeptide (PACAP) has been shown to attenuate the neuronal damage in the hippocampus in a model of global ischemia in rats. The present study examined the neuroprotective action of delayed systemic a dministration of PACAP38 in a model of transient focal ischemia produced by middle cerebral artery occlusion (MCAO) in rats. Methods-We administered PACAP38 as an intravenous bolus (20 nmol/kg body wt ) followed by an intravenous infusion for 48 hours using a micro-osmotic pu mp at a rate of 160 pmol/mu L per hour, beginning 4, 8, or 12 hours after a 2-hour transient MCAO using a filament model. The size of the infarct was determined by examining 2-mm-thick brain sections stained with triphenyltet razolium chloride, followed by image analysis. Control animals received int ravenously 0.1% bovine serum albumin in 0.9% saline as a bolus and infusion at the same time intervals. Results-The administration of PACAP38 beginning 4 hours after MCAO signific antly reduced the infarct size by 50.88%. Treatment with PACAP38 starting 8 or 12 hours after the onset of ischemia did not result in a significant re duction of the infarct size, although infarct volumes tended to be smaller than in the control groups. Conclusions-Systemic administration of PACAP38 should be clinically useful for reducing brain damage resulting from stroke even when administration is delayed for several hours.