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

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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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
StatePublished - Jun 1 2003
Externally publishedYes

Fingerprint

Opioid Receptors
Nitric Oxide
Ischemia
Reperfusion
Brain Ischemia
1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine
Corpus Striatum
Citrulline
Rheology
Microdialysis
Halothane
Arginine
Wistar Rats
Weights and Measures
Wounds and Injuries

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Neuroprotective κ-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats. / Goyagi, Toru; Toung, Thomas J K; Kirsch, Jeffrey R.; Traystman, Richard J.; Koehler, Raymond C.; Hum, Patricia D.; Bhardwaj, Anish.

In: Stroke, Vol. 34, No. 6, 01.06.2003, p. 1533-1538.

Research output: Contribution to journalArticle

Goyagi, Toru ; Toung, Thomas J K ; Kirsch, Jeffrey R. ; Traystman, Richard J. ; Koehler, Raymond C. ; Hum, Patricia D. ; Bhardwaj, Anish. / Neuroprotective κ-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats. In: Stroke. 2003 ; Vol. 34, No. 6. pp. 1533-1538.
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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.",
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AU - Goyagi, Toru

AU - Toung, Thomas J K

AU - Kirsch, Jeffrey R.

AU - Traystman, Richard J.

AU - Koehler, Raymond C.

AU - Hum, Patricia D.

AU - Bhardwaj, Anish

PY - 2003/6/1

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N2 - 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.

AB - 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.

KW - Cerebral ischemia, focal

KW - Infarcts

KW - Rats

KW - Receptors, opioid, kappa

KW - Reperfusion

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