Exercise modulation of BDNF/TrkB signaling in Parkinson's disease: an evidence-calibrated review of neuroprotective mechanisms, biomarker limitations, and translational gaps.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and persistent motor and non-motor impairment. Exercise has emerged as a promising and helpful adjunctive strategy for PD because it improves functional outcomes and may engage biological processes related to neuroprotection and neuroplasticity. Among these mechanisms, brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) signaling have received increasing attention. This review summarizes pathological alterations of BDNF/TrkB signaling in PD and evaluates how exercise may influence this system to support neuronal survival, synaptic plasticity, and microenvironmental homeostasis. Evidence from animal studies suggests that the phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways are mainly supported by preclinical PD exercise studies that assessed dopaminergic preservation, downstream pathway activation, and behavioral recovery. In contrast, phospholipase Cγ (PLCγ)-related signaling, TrkB isoform-specific regulation, astrocyte-dependent mechanisms, and trophic trafficking remain less clearly defined. This review also emphasizes key translational gaps, including peripheral BDNF biomarker limitations, the mismatch between human biomarker studies and animal mechanistic studies, and the need to match exercise prescriptions with specific BDNF/TrkB-related mechanisms.