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(Stroke. 2003;34:1533.)
© 2003 American Heart Association, Inc.

Original Contributions

Neuroprotective -Opioid Receptor Agonist BRL 52537 Attenuates Ischemia-Evoked Nitric Oxide Production In Vivo in Rats

Toru Goyagi, MD; Thomas J.K. Toung, MD; Jeffrey R. Kirsch, MD; Richard J. Traystman, PhD; Raymond C. Koehler, PhD; Patricia D. Hurn, PhD Anish Bhardwaj, MD

From the Departments of Anesthesiology/Critical Care Medicine (T.G., T.J.K.T., J.R.K., R.J.T., R.C.K., P.D.H., A.B.) and Neurology (J.R.K., A.B.), Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Anish Bhardwaj, MD, Neuroscience Critical Care Division, Meyer 8-140, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail abhardwa{at}jhmi.edu

Background and Purpose— -Opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl) methylpiperidine], on infarct volume and nitric oxide production after transient focal ischemia in the rat.

Methods— With the use of the intraluminal filament technique, halothane-anesthetized male Wistar rats (weight, 250 to 300 g) were subjected to 2 hours of focal cerebral ischemia confirmed by Doppler flowmetry. In a blinded randomized fashion, rats were treated with intravenous saline or 1 mg/kg per hour BRL 52537 infusion, initiated 15 minutes before occlusion and maintained until 2 hours of reperfusion. In a second experiment, rats were treated during reperfusion with saline or 1 mg/kg per hour BRL 52537, initiated at onset of reperfusion and continued for 22 hours. In a final experiment, in vivo striatal nitric oxide production was estimated via microdialysis by quantification of citrulline recovery after labeled arginine infusion in striatum of intravenous BRL 52537– or saline-treated rats.

Results— In rats treated with BRL 52537 during ischemia and early reperfusion, infarct volume was significantly attenuated in cortex (16±6% versus 40±7% of ipsilateral cortex in saline group) and in caudoputamen (30±8% versus 66±6% of ipsilateral caudoputamen in saline group). Infarct volume was also reduced by treatment administered only during reperfusion in cortex (19±8% in BRL 52537 group [n=10] versus 38±6% in saline group) and in caudoputamen (35±9% versus 66±4% in saline group). BRL 52537 treatment markedly attenuated NO production in ischemic striatum compared with saline-treated controls.

Conclusions— These data demonstrate that (1) the selective KOR agonist BRL 52537 provides significant neuroprotection from focal cerebral ischemia when given as a pretreatment or as a posttreatment and (2) attenuation of ischemia-evoked nitric oxide production in vivo may represent one mechanism of ischemic neuroprotection.

Key Words: cerebral ischemia, focal • infarcts • receptors, opioid, kappa • reperfusion • rats

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