Dihydromyricetin Protects Against MPTP-induced Model Of Parkinson’s Disease Via Suppressing Glycogen Synthase Kinase-3 Beta Activity

Objective: Dihydromyricetin(DHM),a natural flavonoid compound extracted from the fruit Ampelopsis grossedentata,exerts various pharmacological effects.Our study was designed to investigate the neuroprotective effects of DHM in MPTP-induced model of Parkinson’s disease and potential molecular mechanisms.Methods: Male mice were intraperitoneally injected 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)for 7 d to induce PD.Mice were treated with either 5 or 10 mg/kg for 13 d(3 d before the start of MPTP,during MPTP administration 7 d and 3 d after the end of MPTP).Motor function were evaluated with behavioral tests(locomotor activity,pole test,rotarod test),then mice were sacrificed,brain tissue were collected for immunofluorescence staining and Western blotting.In vivo,MES23.5 cells were treated with MPP+ and DHM,evaluated with cell viability assay,reactive oxygen species(ROS),apoptosis analysis and Western blotting.In addition,we use microglial BV2 cells lines,and treatment with DHM and LPS.The production of pro-inflammatory mediators in microglial cells were assessed by Western blotting,qPCR and ELISA.Results: In vivo,DHM promotes MPTP-induced behavioral motor recovery and protect against dopaminergic neuron loss.The protein expression of TH and VMAT-2,GSK3β-ser-9 in the striatum and substantia nigra pars compacta(SNC)was significantly increased by treatment with DHM compare to PD model group.In vitro study demonstrated that DHM attenuated MPP+-induced neuron cells apotosis,ROS production.DHM increased GSK3β-ser-9 in dose-and time-dependent manner.Moreover,qRT-PCR and ELISA showed that DHM decrease the mRNA and protein levels of inflammation factors in BV2 cells activated by LPS.The translocation of NF-κB(p65)to the nucleus was obviously inhibited by DHM in LPS-treated BV2 cells.Conclusion: Our study suggested that DHM protects DA neurons modulating PI3K/Akt/GSK-3β pathway.In addition,DHM attenuates inflammatory responses of LPS-activated BV2 microglia.DHM may be a potential agent for PD.