BDNF-TrkB signalling: a neurotrophic pathway to cardiovascular protection.

Abstract

The brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling axis has emerged as a promising frontier in cardiovascular research, particularly in the context of myocardial ischemia/reperfusion (I/R) injury. Originally recognized for its neuroprotective functions, BDNF is now gaining recognition for its cardioprotective properties, including anti-apoptotic effects, improved cardiomyocyte survival, and enhanced contractile function. Acting predominantly through TrkB, BDNF attenuates ischemia-induced apoptosis by downregulating caspase-3 and cleaved caspase-9, while simultaneously promoting cardiomyocyte differentiation and proliferation. Intriguingly, under hypoxic conditions, a shift from p75NTR to TrkB receptor activity amplifies these protective effects. Moreover, BDNF modulates intracellular calcium handling by activating Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), contributing to efficient cardiac muscle contraction and relaxation. Paralleling its role in neurons, BDNF-TrkB signaling may also influence mitochondrial dynamics, energy metabolism, and ATP synthesis, potentially aiding in myocardial recovery. Activation of downstream pathways such as PI3K/Akt/mTOR further suggests a role in metabolic reprogramming, though these effects in cardiac tissue require further validation. Despite growing preclinical evidence, the precise molecular interplay between BDNF's anti-apoptotic, metabolic, and calcium-regulatory roles in the heart remains incompletely understood. Future research should focus on elucidating these mechanisms across cardiac cell types and disease contexts to fully harness the therapeutic potential of BDNF-TrkB modulation. Such strategies may pave the way for personalized, neurotrophin-based interventions in the treatment of ischemic heart disease.