Ischemic Neuroprotection With Selective κ-Opioid Receptor Agonist Is Gender Specific

Abstract

We demonstrated previously that treatment with selective kappa-opioid receptor (KOR) agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection, and (2) attenuates ischemia-evoked NO production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male but not in the female rodent model of focal ischemic stroke. We tested the hypothesis that BRL provides significant neuroprotection from transient focal ischemia in male but not in female rats. Halothane-anesthetized adult male and female Wistar rats (250 to 275 g) were subjected to 2 hours of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. In the first experiment, male and female rats were treated in a blinded randomized fashion with vehicle saline or 1 mg/kg per hour BRL infusion started at the onset of reperfusion and continued for 22 hours. In the second experiment, ovariectomized (OVX) female rats were treated with vehicle or BRL. Infarct volume in the cortex and caudoputamen (CP) complex was assessed by triphenyl tetrazolium chloride staining at 72 hours after MCAO. Infarct volume (percentage of ipsilateral structure; mean+/-SEM) was attenuated significantly in male rats with BRL treatment (cortex 23+/-5%; CP 44+/-6%; n=15) compared with vehicle-treated male rats (cortex 38+/-4%; CP 66+/-4%; n=15) but not in female rats (BRL-cortex 26+/-6; CP 55+/-8%; vehicle-cortex 26+/-5; CP 62+/-5%; n=10 each). Neurologic deficit score was improved in BRL-treated male rats but not in female rats. Infarct volume was not different in OVX female rats treated with vehicle or BRL. These data: (1) demonstrate that this dose of selective KOR agonist provides ischemic neuroprotection in male but not female rats, (2) demonstrate that the lack of protection by BRL is not attributable to circulating ovarian hormones, and (3) highlight the importance of using animal models of both sexes in preclinical studies of experimental ischemia.