title: Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity.
abstract: OBJECTIVE
  Doxorubicin (DOX) is an effective anticancer drug; however, its clinical use is limited by its cardiotoxic effect. Adenosine was proved to mediate anti-inflammatory effects and protected from myocardial ischemia/reperfusion injury. So the present work was designed to examine the effectiveness of a selective A3 adenosine receptor agonist (Cl-IB-MECA) in DOX-induced cardiotoxicity and to elucidate the underlying mechanisms via studying its effect on different oxidative stress, inflammatory and apoptotic markers.
  
  
  METHODS
  Firstly the potential cardioprotective dose of Cl-IB-MECA was screened in male Wistar rats at different doses (20, 40 and 80 µg/kg; i.v) against a single dose of DOX (15 mg/kg; i.p). Secondly, the dose of 40 µg/kg Cl-IB-MECA was selected for further assessment of the cardioprotective mechanisms.
  
  
  RESULTS
  Cl-IB-MECA at a dose 40 µg/kg (i.v) protects against DOX-induced bradycardia, elevated creatine kinase isoenzyme-MB and histopathological changes. Also, it significantly ameliorates oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. Additionally, DOX provoked inflammatory responses by increasing the expressions of nuclear factor kappa B and the levels of tumor necrosis factor alpha. Cl-IB-MECA pretreatment significantly inhibited these inflammatory responses. Furthermore, DOX induced apoptotic tissue damage by increasing cytochrome c expressions which was suppressed by Cl-IB-MECA pretreatment.
  
  
  CONCLUSIONS
  Cl-IB-MECA protects against DOX-induced cardiotoxicity through restoration of the oxidant/antioxidant status and consequential suppression of DOX-induced inflammatory responses and abrogation of the resultant apoptotic signals.
authors.affiliation: Cardiac Surgery Hospital, Ain Shams University, Cairo, Egypt.
authors.forename: Aya
authors.initials: A
authors.lastname: Galal
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Wesam M
authors.initials: WM
authors.lastname: El-Bakly
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy for Girls, Al Azhar University, Cairo, Egypt.
authors.forename: Ekram Nemr Abd
authors.initials: EN
authors.lastname: Al Haleem
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbasia, Cairo, Egypt. ebtehal_dm@yahoo.com.
authors.forename: Ebtehal
authors.initials: E
authors.lastname: El-Demerdash
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D066126:Cardiotoxicity / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D043684:Receptor, Adenosine A3 / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D043684:Receptor, Adenosine A3; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D004317:Doxorubicin; D000241:Adenosine
keywords: Adenosine A3 receptor agonist; Cardiotoxicity; Doxorubicin; Oxidative stress