Narrative review synthesizing preclinical (mostly rodent) evidence that exercise-released exerkines—including BDNF, irisin, cathepsin B, IL-6, and IGF-1—modulate neurogenesis, synaptic plasticity and neuroinflammation and could underlie exercise’s benefits in neurodegenerative and mental disorders.

Identifies actionable molecular mediators and biomarkers that point to exercise-mimetic therapeutic strategies for neuroprotection relevant to Parkinson’s disease, but its translational value is limited by reliance on rodent data and lack of direct PD-specific mechanistic or clinical evidence.

Neurodegenerative and mental disorders impose significant global disease burdens and pose serious social and economic challenges. Physical exercise (PE) exerts beneficial effects on brain health, contributing to a reduction in the risk of Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and post-traumatic stress disorder (PTSD). To understand these effects of PE, a variety of molecules released from various tissues in response to PE have been discovered, which are collectively called 'exerkines'. In particular, the skeletal muscle acts as an endocrine organ, secreting exerkines and is included in the category of myokines that facilitate direct or indirect crosstalk between the muscle and the brain. Although muscles actively interact with organs such as the liver, pancreas, and adipose tissue, the precise mechanisms of muscle-brain communication have yet to be fully elucidated. In the skeletal muscle, the types of exerkines secreted and their effects vary depending on the PE modality. Furthermore, these exerkines can cross the blood-brain barrier (BBB) to exert direct effects or act indirectly via molecular signaling pathways, contributing to the modulation of the brain microenvironment, attenuation of neuroinflammation, and neurodegeneration. Previous studies have indicated that brain-derived neurotrophic factor (BDNF), irisin, cathepsin B (CTSB), interleukin-6 (IL-6), and insulin-like growth factor 1 (IGF-1) are involved in enhancing cognitive performance and improving behavioral outcomes by promoting neurogenesis and synaptic plasticity. This review comprehensively discusses the effects of exerkines on the brain and the physiological responses manifested in neurodegenerative and mental disorders focusing primarily on findings from rodent models. Based on these insights, this review proposes future research directions to translate preclinical findings into therapeutic strategies.