title: Protective effect of PNU-120596, a selective alpha7 nicotinic acetylcholine receptor-positive allosteric modulator, on myocardial ischemia-reperfusion injury in rats.
abstract: The cholinergic anti-inflammatory pathway has been found to exert a protective role in myocardial ischemia-reperfusion injury (MIRI). Alpha7 nicotinic acetylcholine receptor (α7nAChR) is a regulator of cholinergic anti-inflammatory pathway; however, little information is available on the effect of α7nAChR on MIRI. In the present study, we hypothesized that 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596), a potent positive allosteric modulator of α7nAChR, could play a protective role on MIRI. Fifty-five rats were randomly assigned into 4 groups: Sham group, ischemia-reperfusion group, PNU-120596 group, α-bungarotoxin group. Compared with ischemia-reperfusion group, PNU-120596 treatment markedly decreased infarct size, ultrastructural damage, serum creatine kinase, and lactate dehydrogenase. Serum proinflammatory cytokine production, myocardium endothelial activation and neutrophil infiltration, myocardium malondialdehyde were also significantly decreased, accompanied by increased myocardium superoxide dismutase production, in the PNU-120596 group compared with the ischemia-reperfusion group. Meanwhile, we observed a significant inhibition of nuclear factor kappa B activation in PNU-120596 group compared with ischemia-reperfusion group. Pretreatment of α7nAChR-selective antagonist, α-bungarotoxin, abolished all the protective effects of PNU-120596 on MIRI. In conclusion, PNU might have a protective effect against MIRI. Its action mechanisms might be involved in the inhibition of inflammatory responses, attenuation of lipid peroxidation, and suppression of nuclear factor kappa B activity.
authors.affiliation: Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Hubei, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Zong-Ze
authors.initials: ZZ
authors.lastname: Zhang
authors.forename: Jia
authors.initials: J
authors.lastname: Zhan
authors.forename: Xiang-Hu
authors.initials: XH
authors.lastname: He
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Song
authors.forename: Yan-Lin
authors.initials: YL
authors.lastname: Wang
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007555:Isoxazoles / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D016207:Cytokines; D007555:Isoxazoles; D016328:NF-kappa B; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor