title: Lack of protection with a novel, selective melanocortin receptor subtype-4 agonist RY767 in a rat transient middle cerebral artery occlusion stroke model.
abstract: Previous studies utilizing alpha-melanocyte-stimulating hormone (alpha-MSH) or the synthetic analog [Nle(4), D-Phe(7)] alpha-MSH have reported beneficial effects in animal models of ischemic stroke, with the latter studies suggesting melanocortin receptor subtype-4 (MC4R) activation as a protective mechanism. The present study directly addresses the hypothesis that MC4R activation may ameliorate ischemic brain injury by assessing the efficacy of a novel small molecule MC4R agonist RY767, administered in a pharmacokinetically guided and pharmacologically validated dosing regimen, in a rat stroke model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats were subjected to 90-min tMCAO followed by 72 h of reperfusion. Treatments were i.p. pretreatment with MK-801 (15 min prior to occlusion, positive control), or combined i.v. and p.o. daily administrations of vehicle, dextrose (negative control) or RY767 in blinded fashion initiated 2 h after occlusion. Infarct volume in MK-801-treated rats (158.7 +/- 22.3 mm(3)) was reduced significantly compared to vehicle infarct volume (243.4 +/- 12.5 mm(3)), whereas infarct volumes in dextrose- (224.3 +/- 16.5 mm(3)) and RY767- (262.1 +/- 19.2 mm(3)) treated rats did not differ from vehicle infarct volume. These results indicate that selective MC4R activation provides no significant neuroprotection, as reflected by infarct volume, in a rat stroke model utilizing a 90-min ischemic insult.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Rahway, N.J., USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Regan
authors.forename: Cherrie
authors.initials: C
authors.lastname: Shepherd
authors.forename: Alison
authors.initials: A
authors.lastname: Strack
authors.forename: David
authors.initials: D
authors.lastname: Weinberg
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Ye
authors.forename: Patrick
authors.initials: P
authors.lastname: Pollard
authors.forename: Tung
authors.initials: T
authors.lastname: Fong
authors.forename: Ian
authors.initials: I
authors.lastname: Reynolds
authors.forename: Joseph
authors.initials: J
authors.lastname: Lynch
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology / Q000517:prevention & control*; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D015427:Reperfusion Injury / Q000503:physiopathology
chemical_list: C534911:N-(1-(2-(4-((1-tert-butyl-3-(2,4-difluorophenyl)piperidin-4-yl)carbonyl)piperazin-1-yl)-4-chloro-5-methylphenyl)ethyl)-N-isopropylacetamide; D018696:Neuroprotective Agents; D010879:Piperazines; D010880:Piperidines; D044105:Receptor, Melanocortin, Type 4; D016291:Dizocilpine Maleate