Efficient

TherapeuticbenefitofTH—engineeredmesenchymalstemcellsfor

    ;Parkinson’sdisease.

    ;LuL,ZhaoC,LiuYSunX,DuanC,JiM,ZhaoH,XuQ,YangH

    ;BeijingInstituteforNeuroscience,TheBeijingCenterofNeuralRegenerationandRepairing,CapitalUniversityofMedicalSciences,

    ;Beijing100054,P.R.China.

    ;Thepresentstudywasdesignedtoassessthepotentialofmarrowstromalcells(MSCs)todelivertherapeuticgenes

    ;tothebrainandresultinbiologicallysignificantfunctionalrecovery.Thetyrosinehydroxylase(TH)genewas

    ;transfectedtoMSCswithanadeno.associatedvirusfAAV1vector.MSCsexpressingTHgeneweretransplanted

    ;intothestriatumofParkinson’sdiseasefPD1rat.Theasynvnetricrotationofthesemodelsafterapomorphine

    ;administrationwasdetectedeveryweekaftertransplantatiOn.Sixweeksaftergrafting,alaimalsweresacrificed.

    ;SomebrainsweresectionedtodOTHilammnohistochelnistry.Theotherswereusedtodetectthedoparninelevels

    ;byhigh—performanceliquidchromatographandelectrochemicaldetection

(HPLC—ECD).Theresultsshowedthat

    ;MSCsmultiplyrapidlyandformedfibroblastcolony—formingunitsinprima

    ryculture.Thegeneexpressioneffi—

    ;ciencywasabout75%.TheroundsofasymmetricrotationafterapomorphineadlnilfistrationdecreasedafterTH.

    ;engineeredMSCsweregrafted.HistologicalexaminationshowedthatTHgenewasexpressedaroundthetransplan—

    ;tationpoints.ThedopaminelevelinthelesionedstriatumofratsinjectedwithTH—MSCswassignificantlygreater

    ;thanthatinratstreatedwithLacZ—MSCsfP<0.05).Allthedatademonstra

    tedthatMSCscouldreadilybegeneti—

    ;callyengincered.Therefore,MSCscouldbeusefulgenedeliveryvehiclesofgenetherapyforParkinson’sdisease.

    ;BrainResProtoc.2005,15(1)=46—51.(impactfactor:1.816)

    ;Efficienttherapeuticgeneexpressioninculturedrathippocampalneurons ;mediatedbyhumanfoamyvirusvectors:apotentialforthetreatmentof ;neurologicaldiseases.

    ;LiuW,HeX,CaoZ,ShengJ,LiuH,LiZ,LiW

    ;KeyLaboratoryofVirology,MinistryofEducation,CollegeofLifeSciences,WuhanUniversity,Wuhan,People’sRepublicof

    ;China.

    ;Vectorsderivedfromhunaanfoamyvirus(HFV),withtheirnonpathogenicna

tureandawidetissuetropism,have

    ;beensuccessfullyusedasretroviralgenetransfervehicles.However,transductionofprimaryhippocampalneurons

    ;(HNs)withHFVvectorshaslittlebeenstudied.Toinvestigatethepotentialof

    derivedvectoringenetherapy HFV—

    ;forneurologicaldiseases,efficientforeigngeneexpressioninculturedratHNswasfirstdemonstratedbysuccessful

    ;enhancedgreenfluorescentprotein(EGFPtransductionthroughaHFVvectorbearingallEGFPexpressioncassette.

    ;Furthcrmore,wetestedtheeffectonHNsthatweretransducedbyanovelHFVvectorexpressingthehuman

    ;?———

    ;46?———

    ;

    ;ghtamicaciddecarboxylase(GAD)eDNA,atherapeuticgeneforneurologicaldisorderssuchasepilepsyand

    ;Parkinson’Sdisease.ThetransducedHNsshowedsignificantincreaseinisoform—specificexpressionofGAD,

    ;synthesisofgamma—anainobutyricacid(GABA)andstimulation—evoke

    dGABArelease.Thesefindingsindicatedfor

    ;thefirsttimethatculturedratHNscouldbeefficientlytransducedbyHFVvectors,andtheGAD—expressingHFV

    ;vectorhaspotentialtherapeuticvalueinthetreatrnentofneurologicaldiseases.Copyright2005S.KargerAG,Basel

    335.(impactfactor:1.776) ;lntervirology.2005,48(5~329—

    ;ValproatepretreatmentprotectsdopaminergicneuronsfromLPS—induced

    ;neurotoxicityinratprimarymidbraincultures:roleofmicroglia. ;PengGS,LiG,TzengNS,ChenPS,ChuangDM,HsuYD,YangS,HongJS ;DepartmentofNeurology,Tri—ServiceGeneralHospital,NationalDefense

    MedicalCenter,Taipei,Taiwan,

    ;Parkinson’SdiseaseisaneurOdegeneratiVedisordercharacterizedbyprogressivedegenerationofdopaminergic

    ;(DA)neuronsinthesubstantianigra.Accumulatingevidencesupportsthenotionthatneuroinflalranationisinvolved

    ;inthepathogencsisofthisdisease.Valproate(VPA)haslongbeenusedforthetreatmentofseizuresandbipolar

    ;mooddisorder.InvivoandinvitrostudieshavedemonstratedthatVPAhasneuroDrotectiveandneurotrophic

    ;actions.Inthisstudy,usingprimaryneuron—gliaculturesfromratmidbrain,

    wedemonstratedthatVPAisapotent

    ;neuroprotectiveagentagainst1ipopolysaccharide(LPS)一

    inducedneurotoxicity.Resultsshowedthatpretreatment

    ;with0.6naNVPAfor48hrobustlyattenuatedLPS—induceddegenerationof

    dopaminergicneuronsasdeterminedby

    ;[(3)H]dopamineuptakeandcountingofthenumberofTH—irneurons.TheneuroprotectiveeffectofVPAwas

    dependentandwasmediated,atleastinpart,throughadecrea;concentration—

    seinlevelsofpro—inflammatoryfactors

    ;releasedfromactivatedmicroglia.Specifically,LPS—inducedincreaseinthereleaseofTNFa,NO,andintracelhlar

    ;reactiveoxygenspecieswasmarkedlyreducedinculturespretreatedwithVP

    A.Theseanti—inflammatoryeffectsof

    ;VPAweretimeandconcentration—dependentcorrelatedwithadecreaseinthenumberofmicroglia.Thus,our

    ;resultsdemonstratethatprotractedVPApretreatmentprotectsdopaminergic

    neuronsfronlLPS--inducedneurotox--

    ;icitythroughareductioninlevelsofreleasedpro—inflan-maatoryfactors,andfurthersuggestthattheseanti—inflam—

    ;matoryeffectsmaybccontributedbyVPA—inducedreductionofmicrogliacellnumber.Takentogether,ourstudy

    ;reinforcestheviewthatVPAmayhaveutilityintreatingParkinson’Sdisease.

    ;MolBrainRes.2005,134(1):162—169.(impactfactor:1.585) ;--——

    ;47--——

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