title: Brain-derived neurotrophic factor attenuates doxorubicin-induced cardiac dysfunction through activating Akt signalling in rats.
abstract: The clinical application of doxorubicin (Dox) is limited by its adverse effect of cardiotoxicity. Previous studies have suggested the cardioprotective effect of brain-derived neurotrophic factor (BDNF). We hypothesize that BDNF could protect against Dox-induced cardiotoxicity. Sprague Dawley rats were injected with Dox (2.5 mg/kg, 3 times/week, i.p.), in the presence or absence of recombinant BDNF (0.4 μg/kg, i.v.) for 2 weeks. H9c2 cells were treated with Dox (1 μM) and/or BDNF (400 ng/ml) for 24 hrs. Functional roles of BDNF against Dox-induced cardiac injury were examined both in vivo and in vitro. Protein level of BDNF was reduced in Dox-treated rat ventricles, whereas BDNF and its receptor tropomyosin-related kinase B (TrkB) were markedly up-regulated after BDNF administration. Brain-derived neurotrophic factor significantly inhibited Dox-induced cardiomyocyte apoptosis, oxidative stress and cardiac dysfunction in rats. Meanwhile, BDNF increased cell viability, inhibited apoptosis and DNA damage of Dox-treated H9c2 cells. Investigations of the underlying mechanisms revealed that BDNF activated Akt and preserved phosphorylation of mammalian target of rapamycin and Bad without affecting p38 mitogen-activated protein kinase and extracellular regulated protein kinase pathways. Furthermore, the beneficial effect of BDNF was abolished by BDNF scavenger TrkB-Fc or Akt inhibitor. In conclusion, our findings reveal a potent protective role of BDNF against Dox-induced cardiotoxicity by activating Akt signalling, which may facilitate the safe use of Dox in cancer treatment.
authors.affiliation: Institute of Clinical Pharmacology, The Second Affiliated Hospital (Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions), Harbin Medical University, Harbin, China.|Heilongjiang Academy of Medical Science, Harbin, China.
authors.forename: Pengzhou
authors.initials: P
authors.lastname: Hang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital (Key Laboratory of Cardiac Diseases and Heart Failure), Harbin Medical University, Harbin, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, The First Affiliated Hospital (Key Laboratory of Cardiac Diseases and Heart Failure), Harbin Medical University, Harbin, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Cardiology, The First Affiliated Hospital (Key Laboratory of Cardiac Diseases and Heart Failure), Harbin Medical University, Harbin, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital (Key Laboratory of Cardiac Diseases and Heart Failure), Harbin Medical University, Harbin, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Clinical Pharmacology, The Second Affiliated Hospital (Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions), Harbin Medical University, Harbin, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
authors.affiliation: Heilongjiang Academy of Medical Science, Harbin, China.|Department of Cardiology, The First Affiliated Hospital (Key Laboratory of Cardiac Diseases and Heart Failure), Harbin Medical University, Harbin, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000009:adverse effects*; D004562:Electrocardiography; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002316:Cardiotonic Agents; D047428:Protein Kinase Inhibitors; D004317:Doxorubicin; D020813:Receptor, trkB; D051057:Proto-Oncogene Proteins c-akt
keywords: 
  BDNF
  ; 
  mTOR
  ; Akt; Bad; apoptosis; doxorubicin