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Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), is commonly used for studies of human inflammatory demyelinating diseases and has been shown to be suitable for studying the effects of exercise on MS pathophysiology. The present study was conducted to determine the impact of forced swimming and voluntary running wheel exercises before and after the induction of EAE on expression of Nogo-A, NgR, and ROCK genes in the brain tissue. A total of 96 C57BL/6 mice were randomly divided into two groups, namely exercises before (EXb, n = 48) and after (EXa, n = 48) induction of EAE. Each group was divided into four subgroups: Forced Swimming + EAE (n = 12), Voluntary Running Wheel + EAE (n = 12), NoEX-EAE (n = 12), and Control group (n = 12). Animals performed either swimming exercise for 30 min per day or running wheel for one hour per day, five days per week for four weeks. Results of Luxal Fast Blue (LFB) staining demonstrated that the degree of demyelination was significantly less in the experimental exercised compared to NoEX-EAE groups (P < .05). Amazingly, both modes of exercise reduced the severity of MS symptoms in mice exposed to swimming and wheel running, evaluated as body weight, clinical scores, degree of demyelination, and gene expressions, regardless of whether the exercise was performed before or after EAE induction.