Kynurenine Pathway Modulation by Exercise in Multiple Sclerosis: Implications for Neuroprotection and Inflammation

Multiple Sclerosis (MS) is a chronic, inflammatory, and neurodegenerative disease of the Central Nervous System (CNS) that is characterized by immune dysregulation and neuroinflammation. Owing to the generation of neuroactive metabolites, the kynurenine pathway (KP), one of the key pathways of tryptophan metabolism, influences the pathogenesis of MS by regulating immune responses and neuronal homeostasis. KP dysregulation results in the overproduction of neurotoxic metabolites such as quinolinic acid (QUIN), characterized by the loss of homeostasis between the neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., QUIN) metabolites, contributing to neuroinflammation, excitotoxicity, and neurodegeneration. Recent evidence suggests that exercise may serve as a non-pharmacological intervention to modulate KP and limit MS progression. Both acute and chronic exercise, especially high-intensity interval training (HIIT), have been demonstrated to decrease the systemic levels of these neurotoxic KP metabolites and increase the neuroprotective KYNA production. Through the modulation of cytokine profiles toward an anti-inflammatory response and Aryl Hydrocarbon Receptor (AhR) activation that promotes immune tolerance, exercise is also an important regulator of the immune response. These findings imply that exercise normalizes KP homeostasis, decreases neuro-axonal damage and improves neuroprotection in MS, but the mechanisms of exercise-induced KP regulation as well as its long-term therapeutic role in MS treatment need further investigation. This review highlights the therapeutic potential of exercise as a complementary approach to existing drugs to ameliorate neuroinflammation and neurodegeneration in MS.