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

Abstract

BACKGROUND AND PURPOSE:

Kappa-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.

• Authors: Toru Goyagi, Thomas J K Toung, Jeffrey R Kirsch, Richard J Traystman, Raymond C Koehler, Patricia D Hurn, Anish Bhardwaj
• Journal: Stroke (Stroke) Vol. 34 Issue 6 Pg. 1533-8 (Jun 2003) ISSN: 1524-4628 [Electronic] United States
• PMID: 12738895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine
• Neuroprotective Agents
• Piperidines
• Pyrrolidines
• Receptors, Opioid, kappa
• Citrulline
• Nitric Oxide
• Arginine

Topics

• Animals
• Arginine (administration & dosage, metabolism)
• Cerebral Infarction (pathology, prevention & control)
• Citrulline (analysis, biosynthesis)
• Corpus Striatum (blood supply, drug effects, metabolism)
• Disease Models, Animal
• Ischemic Attack, Transient (drug therapy, metabolism, pathology)
• Male
• Microdialysis
• Neuroprotective Agents (pharmacology)
• Nitric Oxide (metabolism)
• Piperidines (pharmacology)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Opioid, kappa (agonists)
• Treatment Outcome