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: Alessandra Ottani, Laura Neri, Fabrizio Canalini, Anita Calevro, Rosario Rossi, Gianni Cappelli, Marco Ballestri, Daniela Giuliani, Salvatore Guarini
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 745 Pg. 108-16 (Dec 15 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 25446929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Cardiotonic Agents
• Cytokines
• Inflammation Mediators
• Melanocortins
• STAT3 Transcription Factor
• Stat3 protein, rat
• Carbon Dioxide
• alpha-MSH
• MSH, 4-Nle-7-Phe-alpha-
• Jak2 protein, rat
• Janus Kinase 2
• Oxygen
• Epinephrine

Topics

• Animals
• Apoptosis (drug effects)
• Carbon Dioxide (blood)
• Cardiopulmonary Resuscitation
• Cardiotonic Agents (administration & dosage, pharmacology)
• Cytokines (metabolism)
• Epinephrine (administration & dosage, pharmacology)
• Heart Arrest (drug therapy, pathology, physiopathology)
• Hemodynamics (drug effects)
• Inflammation Mediators (metabolism)
• Janus Kinase 2 (metabolism)
• MAP Kinase Signaling System (drug effects)
• Male
• Melanocortins (administration & dosage, pharmacology, physiology)
• Oxidative Stress (drug effects)
• Oxygen (blood)
• Rats
• Rats, Sprague-Dawley
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• alpha-MSH (administration & dosage, analogs & derivatives, pharmacology)