Progression of Parkinsons Disease Pathology Is Reproduced by Intragastric Administration of Rotenone in Mice 英文参考文献.docVIP

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Progression of Parkinsons Disease Pathology Is Reproduced by Intragastric Administration of Rotenone in Mice 英文参考文献.doc

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Progression of Parkinsons Disease Pathology Is Reproduced by Intragastric Administration of Rotenone in Mice 英文参考文献

ProgressionofParkinson’sDiseasePathologyIs ReproducedbyIntragastricAdministrationofRotenone inMice FranciscoPan-Montojo1,2,6*,OlegAnichtchik3,YaninaDening1,LillaKnels1,StefanPursche4 ,Roland Jung5,SandraJackson2,GabrieleGille2,MariaGraziaSpillantini3,HeinzReichmann2,RichardH.W. Funk1* 1InstituteofAnatomy,MedicalFacultyCarlGustavCarus,DresdenUniversityofTechnology,Dresden,Germany,2DepartmentofNeurology,MedicalFacultyCarlGustav Carus,DresdenUniversityofTechnology,Dresden,Germany,3CenterforBrainRepair,UniversityofCambridge,Cambridge,UnitedKingdom,4DepartmentofInternal MedicineI,MedicalFacultyCarlGustavCarus,DresdenUniversityofTechnology,Dresden,Germany,5ExperimentalCenter,MedicalFacultyCarlGustavCarus,Dresden UniversityofTechnology,Dresden,Germany,6InternationalMax-PlanckResearchSchool,Max-PlanckInstituteforCellBiologyandGenetics,Dresden,Germany Abstract InpatientswithParkinson’sdisease(PD),theassociatedpathologyfollowsacharacteristicpatterninvolvinginteraliathe entericnervoussystem(ENS),thedorsalmotornucleusofthevagus(DMV),theintermediolateralnucleusofthespinalcord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastricallyadministeredrotenone,acommonlyusedpesticidethatinhibitsComplexIofthemitochondrialrespiratory chain,isabletoreproducePDpathologicalstagingasfoundinpatients.Ourresultsshowthatlowdosesofchronicallyand intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structuresofwild-typemice.Moreover,wealsoobservedinflammationandalpha-synucleinphosphorylationintheENSand DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone],20nM)andmitochondrialComplexImeasurementsshowednosystemicComplexIinhibitionafter1.5months oftreatment.Thesealterationsaresequential,appearingonlyinsynapticallyconnectednervousstructures,treatmenttime- dependentandaccompaniedbyinflammatorysi