Ginsenoside Rg1 is one of the most active ingredients in ginseng,which has been reported to protect dopaminergic neurons and improve behavioral defects in MPTP model,6-OHDA model and rotenone model.However,it is unclear whether Rg1 exerted neuroprotection in LPS-induced sub-acute PD model.In this study,we investigated the neuroprotective effect of Rg1 in the subacute PD mouse model and explored the related mechanisms.Rg1 (10,20,40 mg·kg-1·d-1) was orally administered to mice for 18 days.A sub-acute PD model was established in the mice through LPS microinjection into the substantia nigra (SN) from D8 to D13.We found that Rg1 administration dose-dependently inhibited LPS-induced damage of dopaminergic neurons and activation of glial cells in the substantia nigra pars compacta (SNpc).The neuroprotective effects of Rg1 were associated with the reduction of pro-inflammatory cytokines and the improvement of anti-inflammatory cytokines and neurotrophin in the midbrain.Rg1 shifted the polarization of microglia towards the M2 phenotype from M1,evidenced by decreased M1 markers (inducible NO synthase,CD16,etc.) and increased M2 markers (arginase 1 (Arg1),CD206,etc) in the midbrain.Furthermore,Rg1 administration markedly inhibited nuclear translocation of NF-κB in midbrain microglia.In conclusion,Rg1 protects PD mice induced by continuous LPS injection by inhibiting the nuclear entry of NF-κB and regulating the polarization balance of microglia,shedding new light on a disease-modifying therapy of PD.