Targeting the BDNF/TrkB/CREB pathway: emerging strategies for neuroprotection in Parkinson's disease.

Parkinson’s disease (PD) is characterised by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Among neurotrophic pathways, the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP-response element binding protein (CREB) signalling axis has gained attention as a crucial regulator of neuronal survival, synaptic plasticity, and resistance to neurodegeneration. In PD models and clinical studies, downregulation of BDNF and TrkB expression correlates with disease severity, and CREB activity is suppressed. Therefore, modulating this pathway represents a promising therapeutic strategy. Recent preclinical studies have demonstrated that small-molecule TrkB agonists, such as CF3CN, can restore TrkB phosphorylation and downstream Akt/CREB activation, thereby reducing dopaminergic cell loss and motor deficits. Combined modalities, such as dual intervention with TrkB activation (e.g., CF3CN) and inhibition of deleterious proteases, such as δ-secretase, further enhance neuroprotection by preventing pathological α-synuclein cleavage and boosting BDNF expression. Other agents and strategies under exploration include BDNF mimetics, positive allosteric modulators, exercise, gene therapy, and drugs that stabilise or enhance CREB transcriptional efficacy. Nevertheless, modulation of the BDNF/TrkB/CREB pathway offers the potential to both slow neurodegeneration and promote restorative processes in PD. However, emerging evidence suggests that BDNF upregulation alone may not invariably confirm neuroprotection, as its effects are highly context-dependent and influenced by receptor dynamics and downstream signalling integrity.Further clinical studies are needed to validate these preclinical findings, optimise drug delivery, dosage, and timing, and identify biomarkers that predict response to pathway modulation therapies.