on May 8, 2003
Published online before print May 8, 2003, doi: 10.1161/01.STR.0000072512.30658.E7
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Submitted on December 4, 2002
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. * To whom correspondence should be addressed. E-mail: abhardwa{at}jhmi.edu.
Background and Purpose-- 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.
Accepted on January 2, 2003
Neuroprotective
Toru Goyagi MD; 
-Opioid Receptor Agonist BRL 52537 Attenuates Ischemia-Evoked Nitric Oxide Production In Vivo in Rats
-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.
Key words: cerebral ischemia, focal • infarcts • receptors, opioid, kappa • reperfusion • rats
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