Neuroprotective Effects Of Asiatic Acid Against Parkinson-Like Injury Of SH-SY5Y Cells And Motor Deficient Of Mutant Drosophilas

Parkinson's disease(PD) is a progressive neurodegenerative disorder with a prevalence of 1-2%in people over the age of 50.α-Synuclein is a major protein component of Lewy bodies and Lewy neuritis that are involved in the pathology of PD.Overexpression ofα-Synuclein in cells has been suggested to cause elevation of mitochondrial oxidant radicals and mitochondrial structural and functional abnormalities.Pathogenesis of PD mainly includes oxidative stress,mitochondrial dysfunction,excitotoxicity,calcium overloading,trophic factor deficiency, inflammatory processes,and also geneticfactor.Increasing evidence suggests that both oxidative stress and mitochondrial dysfunction,which interact and amplify each other in a vicious cycle of toxicity leading to neuronal dysfunction and finally cell death.Asiatic acid(AA),a triterpenoid,is an antioxidant and used for depression treatment,but the effect of AA against PD-like damage has never been reported.In the present study,the effects of improving motor dysfunction and lifespan were studied in anα-synuclein transgenic Drosophila Parkinson's model. And then the effects of AA against rotenone,H₂O₂ or glutamate(Glu)-induced cellular injury and mitochondrial dysfunction in SH-SY5Y cells were investigated using MTT assay.ROS generation,Mitochondrial membrane potential(MMP) and the expression of voltage-dependent anion channel(VDAC) were detected with or without AA pretreatment following cellular injury to address the possible mechanisms of AA neuroprotection.Finally,Glu-induced mitochondrial swelling was analyzed to show the direct effect of AA on mitochondria.The results showed that in the drosophila model,AA at 1 mg/100 g diet significantly improved climbing ability and extended life-span.And both treatment and pre-treatment of AA(0.01-100 nmol/L) protected cells against the toxicity induced by rotenone, H₂O₂ or Glu.In addition,AA can scavenge ROS induced by Glu.MMP dissipation following the exposure of rotenone could be blocked by AA treatment.More interestingly,pre-administration of AA inhibited VDAC up-regulation induced by rotenone(100 nmol/L) or H₂O₂(300μmol/L).And AA could protect mitochondria from swelling induced by Glu.These data suggests that AA might be developed as an effective agent for PD prevention or therapy.