Improvement Of New Crystallization Nanoparticles And Sesquiterpenelactones Compound ACT001 On MPTP Induced Parkinson's Disease In Mice

Parkinson's disease(PD)is a common neurodegenerative disease that occurs more frequently in the elderly.Its pathological feature is the degenerative death of nigra dopaminergic neurons,resulting in a significant reduction in striatum dopamine content.The clinical manifestations of Parkinson's disease mainly include decreased exercise capacity,enhanced jitteriness,and stiffness.At the same time,patients may be accompanied by non-motor symptoms such as emotional disturbance,sleep disturbance,and cognitive impairment.Although patients with Parkinson's disease are no different from others in life expectancy,they still bring great troubles to the lives of many people.Levodopa(L-3,4-dihydroxyphenylalanine,LD)is currently the main drug for the treatment of Parkinson's disease,but long-term use will cause a large number of side effects,such as levodopa-induced dyskinesia(LID).Therefore,in this study,in order to reduce the amount of levodopa and its side effects,we conducted relevant studies,as follows:On the one hand,we prepared crystalline nanoparticles(LD crystals)loaded with levodopa by microemulsion crystallization.LD crystals show positive zeta potential,nanometer size and longer levodopa release time.In addition,LD crystals showed a significant improvement effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mouse models.Compared with pure LD treatment,LD crystal administration can increase the number of tyrosine hydroxylase(TH)positive neurons in the substantia nigra striatum pathway,and has a better effect on PD mice's exercise ability and exploration behavior.The research results show that as a new type of nanoparticles,LD crystal is an effective potential drug carrier for drug control and release.On the other hand,the natural product parthenolide(PTL)is the active ingredient of the medicinal plant parthenium(Tanacetum parthenium),which has antioxidant and anti-inflammatory effects.According to its structural modification,MCL has the same properties as PTL and has better stability.ACT001 is MCL in the form of dimethylaminofumarate(DMAMCL),which is beneficial to improve oral bioavailability.We will use the MPTP-induced PD mouse model,combined with LD,to investigate the therapeutic effect of ACT001 on PD mice.It was found that ACT001 nigrostriatal pathway of PD mice,and inhibit the expression of ?-synuclein,astrocyte activation,and inflammatory factor interleukin 1?(IL-1?).At the same time,ACT001 also increased the level of anti-apoptotic factor Bcl-2 and p Akt / Akt ratio in the substantia nigra and striatum,and decreased the expression of pro-apoptotic factors Bax and Caspase3.In addition,studies have shown that NOD(nucleotide binding oligomerization domain)-like receptor family 3(NOD-like receptors)NLRP3 inflammasome activation-induced neuroinflammation is associated with PD development.Our results indicate that ACT001 can reduce MPTP-induced dyskinesia,emotional state,and cognitive deficits in PD mice.In addition,it reduces dopaminergic neurodegeneration in the nigrostriatal pathway and inhibits MPTP-induced oxidative stress,inflammatory response,and activation of NLRP3 inflammasome in PD mouse midbrain.Moreover,it attenuates microglia activation in the nigrostriatal pathway.Overall,our research shows that ACT001 can reduce MPTP-induced neuronal inflammation mediated by NLRP3 in PD mice.In summary,the new nanocrystalline carrier can be used as drug carrier of LD,and sesquiterpene lactone ACT001 can be combined with LD to improve Parkinson's disease.This study is expected to develop a safe and effective PD drug delivery method and combination drug strategy.