Parkinson's Disease Of The Microglia-mediated Neuronal Degeneration Mechanism And Its Drug Intervention Study

Objective 1.Activation of microglia has a major impact on progressive dopaminergic neuronal loss in Parkinson's disease(PD).The present study was undertaken to evaluate the activation profile of microglia and the time phase of neurodegenerative process of dopaminergic neurons in 1-methyl-4-phenyl pyridinium (MPP⁺)-induced hemiparkinsonian rats.2.Then,we sought to assess the combinative treatment of both quenching microglial activation by minocycline and enhancing complexâ… function by coenzyme Q₁₀(CoQ₁₀) in hemiparkinsonian rats.3.Lastly,as an integrative treatment protocol,we synergistically administered triptolide with CoQ₁₀ and examined their efficacy on pathological and behavioral changes in MPP⁺ rat model of PD.Methods The rat model of PD was established by intranigral microinjection of MPP⁺.The degree of microglial activation was measured by immunodensity of OX-42(microglia marker) in the substantia nigra(SN).The numbers of viable dopaminergic neurons was determined by tyrosine hydroxylase(TH) positive neurons in the SN.The behavioral performances were revealed with the number of apomorphine induced rotations,score of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry.Results 1.Intranigrally injected MPP⁺ induced microglial activation,progressive dopaminergic neuronal loss and behavioral abnormalities in rats.There was a negative correlation between the dopaminergic neuronal survival ratio and locomotor performances.2.I.c.v.administration of minocyline exhibited microglial inhibitory, neuroprotective,and behavioral improving effect in MPP+-induced hemiparkinsonian rats.3.Combinative therapy using both minocycline and CoQ₁₀ offered additional therapeutic benefit to MPP⁺ rat model of PD.4.Triptolide treatment significantly inhibited microglial activation,partially prevented dopaminergic cells from death and improved behavioral performances.5.Triptolide exerted additive neuroprotective effects when administered synergistically with CoQ₁₀ by targeting different aspect of the disease phenotype. Conclusion 1.Intranigral injection of MPP⁺ resulted in significant behavioral defects,increased density of OX-42-IR,and depletion of dopaminergic neurons.2. Posttreatment of minocyline decreased OX-42-IR,increased the percentage of TH-immunopositive neurons and ameliorated behavioral defects.Combination therapy using both minocyline and CoQ₁₀ exerted additive neuroprotective effect.3. Triptolide and its combinative therapy with CoQ₁₀ had similar effect as minocyline and CoQ₁₀.Immunohistological results showed that the percentage of TH-immunopositive neurons was significantly higher in the combinative treatment group than any single therapy alone.These results indicate that combinative therapy targeting different disease mechanisms may represent a useful strategy in the treatment of PD.