Brain-Derived Neurotrophic Factor Attenuates Septic Myocardial Dysfunction via eNOS/NO Pathway in Rats.
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ABSTRACT:
SUBMITTER: Zeng N
PROVIDER: S-EPMC5523440 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description: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.
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