Neuroprotective kappa-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats.
OBJECTIVE
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.
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md, USA.
Toru
T
Goyagi
Thomas J K
TJ
Toung
Jeffrey R
JR
Kirsch
Richard J
RJ
Traystman
Raymond C
RC
Koehler
Patricia D
PD
Hurn
Anish
A
Bhardwaj
D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D002956:Citrulline / Q000032:analysis / Q000096:biosynthesis; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D016896:Treatment Outcome
C454101:1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine; D018696:Neuroprotective Agents; D010880:Piperidines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine