title: Adenosine A2A receptor-selective stimulation reduces signaling pathways involved in the development of intestine ischemia and reperfusion injury.
abstract: In the present study, we tested the efficacy of treatment with the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenylethylamino]-50-ethylcarboxamidoadenosine (CGS 21680) on ischemia and reperfusion injury of the multivisceral organs. Ischemia and reperfusion injury was induced in mice by clamping both the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by reperfusion. Sixty minutes after reperfusion, animals were killed for histological examination and biochemical studies. Injured vehicle-treated mice developed a significant increase of ileum TNF-alpha levels, myeloperoxidase activity, and marked histological injury and apoptosis. Ischemia and reperfusion injury of the multivisceral organs was also associated with significant mortality. Reperfused ileum sections from injured vehicle-treated mice showed positive staining for P-selectin and intercellular adhesion molecule 1. The intensity and degree of P-selectin and intercellular adhesion molecule 1 were markedly reduced in tissue sections from injured CGS 21680-treated mice. Ischemia and reperfusion-injured mice that have been treated with CGS 21680 showed also a significant reduction of neutrophil infiltration into the intestine, a reduction of apoptosis, and improved histological status of the intestine and survival. Taken together, our results clearly demonstrate that selective activation of adenosine A2A receptors plays an important role in the regulation of ischemia and reperfusion injury and results put forward the hypothesis that selective activation of adenosine A2A receptors may represent a novel and possible strategy.
authors.affiliation: IRCCS Centro Neurolesi Bonino-Pulejo, School of Medicine, University of Messina, Messina, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Alessia
authors.initials: A
authors.lastname: Melani
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Felicita
authors.initials: F
authors.lastname: Pedata
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D053222:Fas Ligand Protein / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007421:Intestine, Small / Q000293:injuries* / Q000473:pathology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019007:P-Selectin / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D010627:Phenethylamines / Q000627:therapeutic use*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D058908:Adenosine A2 Receptor Agonists; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D016328:NF-kappa B; D019007:P-Selectin; D010627:Phenethylamines; D019253:Proto-Oncogene Proteins c-bcl-2; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D018799:Intercellular Adhesion Molecule-1; D011064:Poly Adenosine Diphosphate Ribose; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D000241:Adenosine