Prolonged opportunity for ischemic neuroprotection with selective kappa-opioid receptor agonist in rats.

Abstract

We have previously demonstrated that pretreatment with selective kappa-opioid agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine], provides ischemic neuroprotection following transient focal ischemia in rats. The present study was undertaken to a) define "therapeutic opportunity" for ischemic neuroprotection with BRL 52537, and b) determine if BRL 52537 attenuates ischemia-evoked efflux of dopamine and its metabolites in the striatum in vivo following transient focal ischemia. Using the intraluminal filament technique, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO). In a blinded, randomized fashion, rats were treated with saline (vehicle) or 1 mg/Kg/hr BRL 52537 infusion for 22 hours, initiated at onset, 2, 4, or 6 hours of reperfusion (Rep). In a separate set of experiments utilizing in vivo microdialysis, extracellular levels of dopamine and its metabolites were determined in the striatum during 2 hours of MCAO and 3 hours of reperfusion. Infarct volume (% of contralateral structure; mean +/-SEM) in cortex was significantly attenuated when BRL 52537 was administered at reperfusion (22+/-6%), 2 hours (21+/-6%), and 4 hours (18+/-5%) compared with controls (39+/-5%). In striatum, infarct volume was significantly attenuated when BRL 52537 was administered at reperfusion (38+/-9%), 2 hours (40+/-8%), 4 hours (50+/-8%), and 6 hours (46+/-9%) as compared with controls (70+/-4%). A 6- to 8-fold increase in dopamine in microdialysates occurred within 40 minutes of MCAO. Pretreatment with BRL 52537 did not alter microdialysate levels of dopamine or its metabolites in the striatum during MCAO and early reperfusion, as compared with saline controls. These data demonstrate that BRL 52537 provides robust ischemic neurprotection with a long therapeutic opportunity (at least 6 hours) without altering ischemia-evoked efflux of dopamine (DA) and its metabolites in striatum during ischemia and early reperfusion.