MotorsystemsII:ThebasalgangliaandDrugsusedforthetreatmentofParkinson’sdisease

Louhaiyan（婁海燕）InstituteofPharmacologySchoolofMedicineShandongUniversitylouhaiyan@1ComponentsofBasalGanglia21.ComponentsofBasalGanglia1.CaudateNucleus(尾狀核）2.Putamen

(殼核）3.GlobusPallidus(GP)

（蒼白球，舊紋狀體）4.Substantia

Nigra

（黑質(zhì)）

ParsCompacta

(SNc)

(致密部）

ParsReticulata(SNr)

（網(wǎng)狀部）5.SubthalamicNucleus(STN)(丘腦底核）

新紋狀體紋狀體32.

Mediumspinyneuroninstriatum

(MSN,中型多棘神經(jīng)元)

1)MSN

isthemainefferentneuronsinstriatum;2)MSN的傳入:

Glu

neuronsincortexDA

neuronsinSNcGABA

neurons

instriatumAch

neuronsinstriatumMSN樹突遠端MSN胞體和

樹突近端4

3)MSNdendritecomposeefferentsystem,withGABAastheneurotransmitter.

4)TwotypesofDAreceptorsonMSN:D1

andD2-R:D1-R:enhancedirectpathway→GPi（蒼白球內(nèi)側(cè)部）D2-R:inhibitindirectpathway→GPe

（蒼白球外側(cè)部）53.CircuitrelatedwiththeBasalganglia’sfunctioninthecontrolofmovement

1)directpathway（直接通路）:

在該通路,當(dāng)新紋狀體活動↑→皮層活動↑,

產(chǎn)生去抑制(disinhibition)現(xiàn)象62)indirectpathway

(間接通路):∵在該通路,新紋狀體活動↑→皮層活動↓?！啻送凡糠值窒苯油穼ζ拥呐d奮作用73)Substantia

nigra-Neostriatumpathway

(黑質(zhì)-新紋狀體通路):

此通路對上述兩通路起調(diào)控作用。DA通過D1受體增強直接通路，通過D2抑制間接通路84.Diseasesrelatedwithdysfunction

ofBasalgangliaParkinsondiseaseHutington’sdisease(Chorea)9AdiseaseismainlymanifestedbyextrapyramidalsystemmotordysfunctionbecauseofdegenerativedisorderofCNS.Parkinson’sDisease10CNSdegenerativediseaseAlzheimer’sdisease(AD,阿爾茨海默病)Parkinson’sdisease(PD,帕金森病)Huntingtondisease(HD,亨廷頓病)Amyotrophiclateralsclerosis(ALS,

肌萎縮側(cè)索硬化癥)11Firstdescribedin1817byanEnglishphysician,JamesParkinson,in“AnEssayontheShakingPalsy.”

“paralysisagitans”(震顫麻痹)Parkinson’sDiseaseHistory

JamesC.Parkinson12ThefamousFrenchneurologist,Charcot,furtherdescribedthesyndromein1868(rigidity)named”Parkinsondisease”.1919:確定病變部位主要在黑質(zhì)1960:發(fā)現(xiàn)與黑質(zhì)紋狀體中DA含量顯著降低有關(guān)Parkinson’sDiseaseHistory

13MuhammadAliinAlantaOlympicParkinson’sDiseaseKatharineHepburn

Michael·J·Fox

Parkinson’sDisease(PD)-Symptoms1.Restingtremor(靜止震顫)2.Bradykinesia(運動遲緩)3.Rigidity(肌肉強直)4.Ataxia(共濟失調(diào))顫，硬，慢，共濟失調(diào)155.OthersAbnormalityofpostureandgaitHandwritingMemoryimpairment,confusion,disorientationCognitivedeficitsDepressionParkinson’s

Disease(PD)-Symptoms1617PresymptomaticphaseOnsetSleepOlfactory*MoodAutonomicsystemDiagnosisEarlynonmotorsymptomsSpecificsymptomsMotorPDsymptoms

DopaminergicneuronlossinPD%Remaining

DopaminergicNeuronsTime(years)NonmotorAdaptedimagereprintedfromNeurotherapeutics,Vol.6,HalperinI,MorelliM,KorczynAD,YoudimMB,MandelSA.BiomarkersforevaluationofclinicalefficacyofmultipotentialneuroprotectivedrugsforAlzheimer'sandParkinson'sdiseases,pages128-140,Copyright2009,withpermissionfromElsevier.*OlfactorydysfunctionmaypredateclinicalPDbyatleast4years.Halperinetal.Neurotherapeutics.2009;6:128-140.Lang.Neurology.2007;68:948-952.Rossetal.AnnNeurol.2008;63:167-173.18

From1997,April11thwassetasWorldParkinson'sDiseaseDay,inmemoryofthebirthdayofJamesParkinson--thedoctorwhodescribedPD.WorldParkinson’sdiseaseday19EpidemiologyofPDThesecondmostcommonneurodegenerativedisorderafterAlzheimer’sdisease(AD).Increasewithage(1%population>65yearsold)Meanageatonset:60yearsold85%ofpatientsareover65yearsold20

Classification1.PrimaryPD：unknown2.Secondary:ParkinsonismCerebralarteriosclerosis

Encephalitis(腦炎)Drugpoison(藥物中毒):氰化物、利舍平、酚噻嗪類及抗抑郁藥等Chemicals:Mn2+、除草劑、殺蟲劑等21EtiologyofPDUnknown:Increasingage(rareinthose<50;earlyoryoungonset)MoreoftentooccurinfamilieswithrelativeswithPDAlpha-synuclein/Parkin/LRRK2/DJ-1etcEnvironmentalfactors(pesticides,ruralresidence)Headtrauma?Infection?Caffeineandsmokinghavebeenfoundtobeprotective22RiskofParkinson’sDiseaseIncreasedriskAgeHighBodyMassIndexMalegenderFamilyhistoryDepressionEnvironmentfactorsrurallivingwell-waterdrinkingweldingheadinjuryDecreasedriskCaffeineintakeSmokingcigarettesAnti-oxidantsindiet23AnimalmodelofPDMPTP6-OHDARotenoneParaquat241.Dopamine(DA)theory

Pathophysiology

DAneuronaldegenerationinsubstantia

nigra

reducedorlackofdopamineinthestriatum25PDPathologyNormalPDsubstantia

nigrasubstantia

nigra26NigrosriaialDopaminePathway27核28當(dāng)DA合成減少或DA神經(jīng)元退化時傳入傳出白質(zhì)背側(cè)腹側(cè)ACh興奮前角運動神經(jīng)元DA抑制前角運動神經(jīng)元前角后角灰質(zhì)Dopaminetheory膽堿能神經(jīng)元多巴胺能神經(jīng)元黑質(zhì)內(nèi)DA能神經(jīng)元發(fā)生退行性變出現(xiàn)PD的癥狀29DopaminetheoryAch黑質(zhì)紋狀體DADA(—)(＋)調(diào)節(jié)運動功能脊髓前角運動神經(jīng)元30

Pathogenesis

DAneuronaldegenerationinsubstantia

nigra(黑質(zhì))1.Dopamine(DA)theory

↓DAsynthesisreducedorlackofdopamineinthestriatum↓thefunctionofDAinthenigro-striatalDApathway↑thefunctionofAch

musculartension31DA氧化代謝H2O2、O-2

ComplexⅠ

抗氧化物（谷胱甘肽）

·OH

、O+2Fe3+促進神經(jīng)膜類脂氧化破壞DA神經(jīng)細胞膜功能黑質(zhì)

Pathogenesis

2.Oxidativestress-freeradicaltheory32TreatmentofParkinson’sdiseaseNocureforPDDopaminergicmedicationNon-dopaminergicmedicationOtherstrategiesSurgicalinterventionRegularexercise33AntiparkinsonismdrugsDAAchDopaminomimeticDrugsCentralAnticholinergicDrugs34AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸脫羧酶35

Ⅰ

DopaminomimeticDrugs

1.

PrecursorofDA

2.SynergeticagentsofL-dopa

(左旋多巴的增效藥）3.DAreceptoragonists

4.DrugsenhancingDArelease361.

PrecursorofDA

——

levodopa（L-dopa,左旋多巴）LevodopaDopamine37【Pharmacologicalactionsandmechanism】PenetrateBBBintothebrainDecarboxylated(脫羧)

byAADCtoDASupplyDAtostriatum

38AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸脫羧酶39【Clinicaluse】widelyusedforalltypesofPDpatients

1.Parkinson’sdisease:symptomatictreatment(1)earlystage:goodandstableeffect80%canbesignificantlyimproved,ofwhich20%recoverdtothenormalstate(2)laterstage:effectgraduallydecreased,littleeffectafter3-5years

40Characteristics:

(1)havegoodeffectonmildandyoungerpatients,lesseffectonsevereandelderlypatients(2)moreeffectiveformusclarrigidityandakinesia

(運動不能),lesseffectiveforrestingtremor,difficulttoimprovethedementia(癡呆)(3)slowonset,initialeffectivetimeis2-3w,1-6mtomosteffective(Emax)41(4)noteffectiveforParkinsoniumcausedby

phenothiazines(吩噻嗪類)antipsychoticdrugs(5)Drugcombination:combinedwithperipheralAADCinhibitor,reducethedosageofL-DOPAby75%

cabidopa(卡比多巴)orbenserazide(芐絲肼)Characteristics:

422.Hepaticcoma(肝昏迷):symptomatictreatmentfalseneurotransmittertheory(偽遞質(zhì)學(xué)說）Levodopametabolizedtonoradrenaline

(NA)toreplacefalseneurotransmitter43食物中芳香族氨基酸脫羧酶酪胺和苯乙胺肝中MAO清除腸菌肝功能血濃度腦組織羥化酶苯乙醇胺羥苯乙胺擬去甲腎上腺素等遞質(zhì)神經(jīng)傳導(dǎo)障礙肝昏迷左旋多巴去甲腎上腺素改善神經(jīng)傳導(dǎo)腦內(nèi)轉(zhuǎn)變44【Pharmacokinetics】1.Absorptionoral,absorbedbysmallintestine,t1/21-3hBioavailabilityisaffectedbygastricemptying,gastricacidpH45

【Pharmacokinetics】2.DistributionandmetabolismLevodopaCOMTreuptakeMAOMAO:單胺氧化酶COMT:兒茶酚胺-O-甲基轉(zhuǎn)移酶3.Elimination:kidney—46【Adversereactions】1.earlyreactions：(1)Gastrointestinaleffect:80%anorexia(厭食),nausea,vomitingtoleranceafterseveralweeks

domperidone(多潘立酮，嗎丁啉)D2-Rblocker(2)Cardiovasculareffects:orthostatichypotension(直立性低血壓)30%arrhythmias—blocker47

【Adversereactions】2.long-termreactions(1)Hyperkinesia(運動過多癥,

dyskinesia,運動障礙):90%(＞2years)

hand,feet,body—abnormalchoreoathetoidmovements

(舞蹈樣手足徐動癥)overstimulationofDA-Rinvoluntarymovement(不自主運動)orofacial(triad)

:sucking,lickingthetongue,chewingDA-Rblocker48(2)Fluctuationsinresponse(癥狀波動):

on-offphenomena40%-80%(3-5years)(3)Psychicdisorders

Clozapine(氯氮平)：D449

【Druginteractions】VitB6:

coenzymeofAADC,increasetheactivityAADCAntipsychoticdrugs:blockDA-RofNigro-striatalsystem,

weakenDAfunction50Levodopa:

TheCornerstoneofPDTherapyLevodopaprovidessubstantialantiparkinsoniansymptomcontrol,andsignificantlyimprovespatientqualityoflife1LevodopaisthemostefficaciousantiparkinsonianmedicationinmoderateandadvanceddiseaseLevodopaprovidesrelativelyrapidsymptomaticbenefits2,3

LevodopaisgenerallywelltoleratedwithfewinitialsideeffectsLevodopacontinuestoprovideantiparkinsonianbenefitsthroughthecourseoftheillnessAllPDpatientseventuallyrequirelevodopatherapy1.LouisED,etal.ArchNeurol.1997;54:260-264.2.OlanowCW,etal.Neurology.2001;56:S1-S86.3.Agidyetal.Lancet.2002;360:575.512.SynergeticagentsofL-dopa

(左旋多巴的增效藥）AADC(氨基酸脫羧酶)inhibitors

cabidopa,benserazide

(芐絲肼)

(2)MAO-Binhibitors

selegiline

(司來吉蘭)(3)COMTinhibitors

nitecapone(硝替卡朋）52MetabolismofL-dopaL-DOPADAAADCCOMT3-OMDL-DOPACarrier3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeriphery53(1)AADC(氨基酸脫羧酶)inhibitors(≠BBB)L-DOPADAAADCCOMT3-OMDL-DOPACarrier3-OMDDAAADCdegradationMAO-BCOMTuptake(3-O-甲基多巴)BBBBrainPeripheryX54(1)AADC(氨基酸脫羧酶)inhibitorsCarbidopa(卡比多巴):

notpenetrateBBB,onlyinhibitperipheryAADC,

increaseL-dopaintothebrain,reducethedosageofL-dopaby75%Benserazide(芐絲肼):

similar

CompoundPreparationsSinemet(息寧，心寧美)

Levodopa:Carbidopa(10:1)Madopar(美多巴)

Levodopa:Benserazide(4:1)55(2)MAO-Binhibitors(＝BBB)L-DOPADAAADCCOMT3-OMDL-DOPACarrier3-OMDDAAADCXdegradationMAO-BCOMTuptake(3-O-甲基多巴)BBBBrainPeriphery56(2)MAO-Binhibitors-Selegiline(司來吉蘭)hypertensivecrisisMAO-B:CNS(nigrostriatal)selegiline(司來吉蘭):BBBpermeablereducetheadministratedL-dopadoseand“on-offresponse”

antioxidanteffectlowdose(＜10mg/d)—onlyinhibitMAO-B→DA↑highdose(＞10mg/d)—inhibitMAO-Atoo→

57(3)COMTinhibitors(≠or＝

BBB)L-DOPADAAADCCOMT3-OMDL-DOPACarrier3-OMDDAAADCXdegradationMAO-BCOMTuptake(3-O-甲基多巴)BBBBrainPeripheryX58Periphery:CNS:DAdegradation↓→DAinCNS↑(3)COMTinhibitors(≠or＝

BBB)L-DOPAdegradation↓3-OMD(3-O-甲基多巴)↓carrieravailableforL-DOPA↑L-DOPAthatreachthebrain↑59nitecapone(硝替卡朋):peripheryTocapone(托卡朋):peripheryandCNS

Entacapone(安托卡朋):periphery(3)COMTinhibitors(≠or＝

BBB)60Dopaminereceptorsfivemainsubtypes:D1~D5

D1-likereceptors:D1,D5excitation

D2-likereceptors:D2,D3,D4inhibition3.DAreceptoragonistsNigro-striatalsystem:

D1-likereceptor(D1,D5)

D2-likereceptor(D2,D3)61Bromocriptine(溴隱亭):

D2agonism,D1partialantagonismPramipexole(普拉克索):D2agonism

Ropinirole(羅平尼咯):D2agonism

Lisuride(利修來得):D2agonism,D1weakantagonism3.DAreceptoragonists62

Bromocriptine

(溴隱亭)1.Smalldose:stimulateD2-likeRintuberoinfundibular（結(jié)節(jié)漏斗部）

reduceprolactin(PRL)andGHrelease2.Largedose:stimulateD2-likeRinsubstantia

nigro-striatal

Uses:PD,hyperprolactinemia

(高催乳素血癥)

acromegaly(肢端肥大癥)634.DrugsenhancingDAreleaseAmantadine(金剛烷胺)Mechanism:

1.↑releaseDAfromdopamine