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Involvement of neurotrophic signaling in doxorubicin-induced cardiotoxicity

Dehua Liao1, Chen Zhang2, Ni Liu1

  • 1Department of Pharmacy, Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China.

Experimental and Therapeutic Medicine
|February 4, 2020
PubMed

Insights

Doxorubicin (DOX) causes heart damage by reducing key neurotrophic factors like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the heart, impacting crucial signaling pathways.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Neuroscience

Background:

  • Doxorubicin (DOX) is a potent chemotherapy agent with dose-dependent cardiotoxicity as a major side effect.
  • The molecular mechanisms underlying DOX-induced cardiotoxicity are not fully understood.
  • Neurotrophic signaling, involving neurotrophins and their receptors, is critical for neuronal and cardiac function, but its role in DOX cardiotoxicity is unexplored.

Purpose of the Study:

  • To investigate the impact of DOX administration on neurotrophic signaling pathways in the heart.
  • To determine the levels of neurotrophins (BDNF, NGF) and their receptors (TrkA, TrkB) in rat hearts following DOX treatment.
  • To elucidate the association between altered neurotrophic signaling and DOX-induced cardiac injury.

Main Methods:

  • Rats were administered DOX intraperitoneally (2.5 mg/kg) seven times every two days.
  • Cardiac injury markers (CK, LDH, troponin T, AST) in serum were measured.
  • Gene and protein expression of BDNF, NGF, TrkA, and TrkB in cardiac tissue were analyzed.
  • Western blotting was used to assess the phosphorylation status of TrkA, TrkB, and downstream kinases (Akt, ERK).

Main Results:

  • DOX treatment significantly elevated cardiac injury markers in serum.
  • Both gene and protein expression of BDNF and NGF were markedly decreased in the heart post-DOX.
  • Serum BDNF levels decreased, while serum NGF levels increased after DOX administration.
  • DOX significantly reduced TrkA and TrkB receptor levels and their phosphorylation ratios (pTrkA/TrkA, pTrkB/TrkB).
  • Downstream signaling pathways, including Akt and ERK phosphorylation, were suppressed by DOX.

Conclusions:

  • Neurotrophic signaling, specifically BDNF/TrkB and NGF/TrkA pathways, is significantly altered by DOX treatment.
  • These alterations in neurotrophic signaling contribute to the development of DOX-induced cardiotoxicity.
  • The findings highlight a novel molecular mechanism linking neurotrophic dysregulation to chemotherapy-induced heart damage.
Keywords:
brain-derived neurotrophic factor/TrkBcardiotoxicitydoxorubicinnerve growth factor/TrkAneurotrophic signaling

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