title: Protective effects of the melanocortin analog NDP-α-MSH in rats undergoing cardiac arrest.
abstract: We previously reported that melanocortins afford cardioprotection in conditions of experimental myocardial ischemia/reperfusion, with involvement of the janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers and activators of transcription (STAT) signalings. We investigated the influence of the melanocortin analog [Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) on short-term detrimental responses to cardiac arrest (CA) induced in rats by intravenous (i.v.) administration of potassium chloride, followed by cardiopulmonary resuscitation (CPR) plus epinephrine treatment. In CA/CPR rats i.v. treated with epinephrine (0.1 mg/kg) and returned to spontaneous circulation (48%) we recorded low values of mean arterial pressure (MAP) and heart rate (HR), alteration of hemogasanalysis parameters, left ventricle low expression of the cardioprotective transcription factors pJAK2 and pTyr-STAT3 (JAK-dependent), increased oxidative stress, up-regulation of the inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and down-regulation of the anti-inflammatory cytokine IL-10, as assessed at 1h and 3h after CPR. On the other hand, i.v. treatment during CPR with epinephrine plus NDP-α-MSH (340 μg/kg) almost completely restored the basal conditions of MAP and HR, reversed metabolic acidosis, induced left ventricle up-regulation of pJAK2, pTyr-STAT3 and IL-10, attenuated oxidative stress, down-regulated TNF-α and IL-6 levels, and improved survival rate by 81%. CA/CPR plus epinephrine alone or in combination with NDP-α-MSH did not affect left ventricle pSer-STAT3 (ERK1/2-dependent) and pERK1/2 levels. These results indicate that melanocortins improve return to spontaneous circulation, reverse metabolic acidosis, and inhibit heart oxidative stress and inflammatory cascade triggered by CA/CPR, likely via activation of the JAK/STAT signaling pathway.
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Neri
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Canalini
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Calevro
authors.affiliation: Division of Cardiology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Division of Nephrology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Cappelli
authors.affiliation: Division of Nephrology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ballestri
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: daniela.giuliani@unimore.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: salvatore.guarini@unimore.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D016887:Cardiopulmonary Resuscitation; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology; D006323:Heart Arrest / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D053486:Melanocortins / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D053486:Melanocortins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D002245:Carbon Dioxide; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D010100:Oxygen; D004837:Epinephrine
keywords: Cardiac arrest; Epinephrine; JAK/ERK/STAT signaling; Melanocortins; Metabolic acidosis; Resuscitation