Neuroprotective κ-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats

Toru Goyagi, Thomas J K Toung, Jeffrey Kirsch, Richard J. Traystman, Raymond C. Koehler, Patricia D. Hum, Anish Bhardwaj

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Background and Purpose - κ-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.

Original languageEnglish (US)
Pages (from-to)1533-1538
Number of pages6
JournalStroke
Volume34
Issue number6
DOIs
Publication statusPublished - Jun 1 2003
Externally publishedYes

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Keywords

  • Cerebral ischemia, focal
  • Infarcts
  • Rats
  • Receptors, opioid, kappa
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

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