Myelin damage and abnormal remyelination processes lead to central nervous system dysfunction.Glial activation-induced microenvironment changes are characteristic features of the diseases with myelin abnormalities.We previously showed that ginsenoside Rg1,a main component of ginseng,ameliorated MPTP-mediated myelin damage in mice,but the underlying mechanisms are unclear.In this study we investigated the effects of Rg1 and mechanisms in cuprizone(CPZ)-induced demyelination mouse model.Mice were treated with CPZ solution(300mg·kg-1·d-1,ig)for 5 weeks;from week 2,the mice received Rg1(5,10,and 20 mg·kg-1·d-1,ig)for 4 weeks.We showed that Rg1 administration dose-dependently alleviated bradykinesia and improved CPZ-disrupted motor coordination ability in CPZ-treated mice.Furthermore,Rg1 administration significantly decreased demyelination and axonal injury in pathological assays.We further revealed that the neuroprotective effects of Rg1 were associated with inhibiting CXCL10-mediated modulation of glial response,which was mediated by NF-KB nuclear translocation and CXCL10 promoter activation.In microglial cell line BV-2,we demonstrated that the effects of Rg1 on pro-inflammatory and migratory phenotypes of microglia were related to CXCL10,while Rg1-induced phagocytosis of microglia was not directly related to CXCL10.In CPZ-induced demyelination mouse model,injection of AAV-CXCL10 shRNA into mouse lateral ventricles 3 weeks prior CPZ treatment occluded the beneficial effects of Rg1 administration in behavioral and pathological assays.In conclusion,CXCL10 mediates the protective role of Rg1 in CPZ-induced demyelination mouse model.This study provides new insight into potential disease-modifying therapies for myelin abnormalities.