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: Pengzhou Hang, Jing Zhao, Li Sun, Minghui Li, Yu Han, Zhimin Du, Yue Li
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 4 Pg. 685-696 (04 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 28098423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Brain-Derived Neurotrophic Factor
• Cardiotonic Agents
• Protein Kinase Inhibitors
• Doxorubicin
• Receptor, trkB
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Brain-Derived Neurotrophic Factor (pharmacology)
• Cardiotonic Agents (pharmacology)
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• DNA Damage
• Doxorubicin (adverse effects)
• Electrocardiography
• Enzyme Activation (drug effects)
• Fibrosis
• Heart (diagnostic imaging, drug effects, physiopathology)
• Heart Ventricles (diagnostic imaging, drug effects, physiopathology, ultrastructure)
• Humans
• Male
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Sprague-Dawley
• Receptor, trkB (metabolism)
• Signal Transduction (drug effects)