Involvement of neurotrophic signaling in doxorubicin‑induced cardiotoxicity

Abstract

Dose dependent cardiotoxicity is the primary side effect of doxorubicin (DOX), but the underlying molecular mechanisms remain unclear. An increasing amount of evidence has demonstrated that neurotrophic signaling plays a pivotal role in both neurons and the heart, but the biological association between neurotrophic signaling and DOX-induced cardiotoxicity remains unknown. The present study determined the level of neurotrophins and their receptors in the heart of rats following DOX administration. DOX was administered 7 times at a dose of 2.5 mg/kg once every 2 days via intraperitoneal injection. The present study revealed that cardiac injury parameters, such as creatine kinase (CK), creatine kinase-myocardial bound, lactate dehydrogenase, troponin T and aspartate transaminase in serum were significantly increased in the DOX group. Both the gene and protein expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the heart were markedly decreased following DOX treatment. Notably, the protein level of BDNF in the serum was inhibited in DOX-treated rats, whereas DOX induced a significant increase in the protein level of NGF in the serum. DOX induced a significant decrease in the level of tropomyosin-associated kinase A (TrkA) and the ratio of pTrkA/TrkA and pTrkB/TrkB. Furthermore, the administration of DOX suppressed downstream protein kinase B and extracellular signal regulated kinase phosphorylation. The present study first demonstrated that BDNF/TrkB signaling and NGF/TrkA signaling were altered by DOX, which indicated that neurotrophic signaling was involved in DOX-induced cardiotoxicity.

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

“…These changes induced by doxorubicin were proven to be associated with augmentation of caspase-3 and caspase-9 activity with enhancement of apoptosis [43]. In addition, it was reported that doxorubicin may reduce the tissue levels of the antiapoptotic proteins such as Bcl2 and NGF-β, and thereby lead to overt cytotoxicity [44,45].…”

The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases

“…Furthermore, ourstudyfurther uncovered that BDNF mimetic, 7,8-DHF, activated the TrkB receptor and attenuated DOX-induced cardiotoxicity and mitochondrial dysfunction in a mouse model [ 14 ]. Consistently, Liao et al reproduced that neurotrophic signaling including both BDNF/TrkB and NGF/TrkAwasaffected by DOX [ 36 ]. Besides, there is now consensus that a number of chemotherapy drugs such as arsenic trioxide cause cardiotoxicity.…”

Do Neurotrophins Connect Neurological Disorders and Heart Diseases?

“…Doxorubicin (DOX)/adriamycin is effective in the treatment of several cancers; however, dose-dependent cardiac adverse reactions, such as heart arrhythmias, irreversible cardiomyopathy, and congestive heart failure, significantly limit its clinical use [ 79 ]. To overcome this, several groups have shown that NTs are involved in the pathogenesis of cardiotoxicity, and NTs play a protective role against cardiac damage through survival signaling [ 80 , 81 ].…”