Ezetimibe alleviates oxidative stress and neuroinflammation in mice with Parkinson's disease induced by MPTP by activating the Nrf2/TREM2 pathway

WEI Lijian; HUA Junkai; LEI Jianming; HUANG Wendong

doi:10.20227/j.cnki.2096-3610.2025.05.008

Abstract：Objective To investigate the neuroprotective effects and underlying mechanisms of the lipid-lowering drug Ezetimibe(Eze)in a Parkinson's disease(PD)model.Methods In vitro,BV-2 murine microglial cells were divided into blank,MPP⁺,and Eze+MPP⁺ groups,and cell viability was measured.Male C57BL/6J mice were used to establish a Parkinson's disease model induced by MPTP.Thirty-six healthy male mice were randomly allocated into three groups(n=12 per group):Control,receiving daily intraperitoneal saline for 5 weeks;MPTP,receiving 25 mg/kg MPTP intraperitoneally twice weekly for 5 weeks;and MPTP+Eze,receiving the same MPTP schedule plus daily intraperitoneal Eze at 10 mg/kg for 5 weeks.Twenty-four hours after the last administration,motor performance was evaluated using the pole,rotarod,and grip-strength tests.The animals were then euthanized,and substantia nigra tissue was collected.Western blot was performed to measure protein levels of nuclear factor erythroid 2-related factor 2(Nrf2),triggering receptor expressed on myeloid cells 2(TREM2),tyrosine hydroxylase(TH),and ionized calcium-binding adapter molecule 1(IBA-1).Interleukin-1 beta(IL-1β)content was determined by Enzyme-Linked Immunosorbent Assay(ELISA),and immunofluorescence staining was used to assess microglial activation.Results In vitro,Eze significantly increased the viability of MPP⁺-challenged BV-2 cells(P<0.05).In vivo,compared with the MPTP group,the MPTP+Eze group showed significant upregulation of Nrf2(P<0.05)and TREM2(P<0.01)expression,suppression of IBA-1 expression,reduced IL-1β secretion(P<0.01),increased TH ⁺ neuron counts(P<0.01),and improved motor performance in pole-climbing,rotarod,and grip strength assays(P<0.05).Conclusion Eze exerts neuroprotective effects on dopaminergic neurons by activating the Nrf2/TREM2 signaling pathway,leading to alleviate oxidative stress and neuroinflammation.