人体结构与功能 18-Motor systems II- the basal ganglia and parkinsons disease学习资料

MotorsystemsII:ThebasalgangliaandDrugsusedforthetreatmentofParkinson’sdisease

Louhaiyan（娄海燕）InstituteofPharmacologySchoolofMedicineShandongUniversitylouhaiyan@1ComponentsofBasalGanglia21.ComponentsofBasalGanglia1.CaudateNucleus(尾状核）2.Putamen

(壳核）3.GlobusPallidus(GP)

（苍白球，旧纹状体）4.Substantia

Nigra

（黑质）

ParsCompacta

(SNc)

(致密部）

ParsReticulata(SNr)

（网状部）5.SubthalamicNucleus(STN)(丘脑底核）

新纹状体纹状体32.

Mediumspinyneuroninstriatum

(MSN,中型多棘神经元)

1)MSN

isthemainefferentneuronsinstriatum;2)MSN的传入:

Glu

neuronsincortexDA

neuronsinSNcGABA

neurons

instriatumAch

neuronsinstriatumMSN树突远端MSN胞体和

树突近端4

3)MSNdendritecomposeefferentsystem,withGABAastheneurotransmitter.

4)TwotypesofDAreceptorsonMSN:D1

andD2-R:D1-R:enhancedirectpathway→GPi（苍白球内侧部）D2-R:inhibitindirectpathway→GPe

（苍白球外侧部）53.CircuitrelatedwiththeBasalganglia’sfunctioninthecontrolofmovement

1)directpathway（直接通路）:

在该通路,当新纹状体活动↑→皮层活动↑,

产生去抑制(disinhibition)现象62)indirectpathway

(间接通路):∵在该通路,新纹状体活动↑→皮层活动↓。∴此通路部分抵消直接通路对皮层的兴奋作用73)Substantia

nigra-Neostriatumpathway

(黑质-新纹状体通路):

此通路对上述两通路起调控作用。DA通过D1受体增强直接通路，通过D2抑制间接通路84.Diseasesrelatedwithdysfunction

ofBasalgangliaParkinsondiseaseHutington’sdisease(Chorea)9AdiseaseismainlymanifestedbyextrapyramidalsystemmotordysfunctionbecauseofdegenerativedisorderofCNS.Parkinson’sDisease10CNSdegenerativediseaseAlzheimer’sdisease(AD,阿尔茨海默病)Parkinson’sdisease(PD,帕金森病)Huntingtondisease(HD,亨廷顿病)Amyotrophiclateralsclerosis(ALS,

肌萎缩侧索硬化症)11Firstdescribedin1817byanEnglishphysician,JamesParkinson,in“AnEssayontheShakingPalsy.”

“paralysisagitans”(震颤麻痹)Parkinson’sDiseaseHistory

JamesC.Parkinson12ThefamousFrenchneurologist,Charcot,furtherdescribedthesyndromein1868(rigidity)named”Parkinsondisease”.1919:确定病变部位主要在黑质1960:发现与黑质纹状体中DA含量显著降低有关Parkinson’sDiseaseHistory

13MuhammadAliinAlantaOlympicParkinson’sDiseaseKatharineHepburn

Michael·J·Fox

Parkinson’sDisease(PD)-Symptoms1.Restingtremor(静止震颤)2.Bradykinesia(运动迟缓)3.Rigidity(肌肉强直)4.Ataxia(共济失调)颤，硬，慢，共济失调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(脑炎)Drugpoison(药物中毒):氰化物、利舍平、酚噻嗪类及抗抑郁药等Chemicals:Mn2+、除草剂、杀虫剂等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当DA合成减少或DA神经元退化时传入传出白质背侧腹侧ACh兴奋前角运动神经元DA抑制前角运动神经元前角后角灰质Dopaminetheory胆碱能神经元多巴胺能神经元黑质内DA能神经元发生退行性变出现PD的症状29DopaminetheoryAch黑质纹状体DADA(—)(＋)调节运动功能脊髓前角运动神经元30

Pathogenesis

DAneuronaldegenerationinsubstantia

nigra(黑质)1.Dopamine(DA)theory

↓DAsynthesisreducedorlackofdopamineinthestriatum↓thefunctionofDAinthenigro-striatalDApathway↑thefunctionofAch

musculartension31DA氧化代谢H2O2、O-2

ComplexⅠ

抗氧化物（谷胱甘肽）

·OH

、O+2Fe3+促进神经膜类脂氧化破坏DA神经细胞膜功能黑质

Pathogenesis

2.Oxidativestress-freeradicaltheory32TreatmentofParkinson’sdiseaseNocureforPDDopaminergicmedicationNon-dopaminergicmedicationOtherstrategiesSurgicalinterventionRegularexercise33AntiparkinsonismdrugsDAAchDopaminomimeticDrugsCentralAnticholinergicDrugs34AADCTH:酪氨酸羟化酶THAADC:L-芳香族氨基酸脱羧酶35

Ⅰ

DopaminomimeticDrugs

1.

PrecursorofDA

2.SynergeticagentsofL-dopa

(左旋多巴的增效药）3.DAreceptoragonists

4.DrugsenhancingDArelease361.

PrecursorofDA

——

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

byAADCtoDASupplyDAtostriatum

38AADCTH:酪氨酸羟化酶THAADC:L-芳香族氨基酸脱羧酶39【Clinicaluse】widelyusedforalltypesofPDpatients

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

40Characteristics:

(1)havegoodeffectonmildandyoungerpatients,lesseffectonsevereandelderlypatients(2)moreeffectiveformusclarrigidityandakinesia

(运动不能),lesseffectiveforrestingtremor,difficulttoimprovethedementia(痴呆)(3)slowonset,initialeffectivetimeis2-3w,1-6mtomosteffective(Emax)41(4)noteffectiveforParkinsoniumcausedby

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

cabidopa(卡比多巴)orbenserazide(苄丝肼)Characteristics:

422.Hepaticcoma(肝昏迷):symptomatictreatmentfalseneurotransmittertheory(伪递质学说）Levodopametabolizedtonoradrenaline

(NA)toreplacefalseneurotransmitter43食物中芳香族氨基酸脱羧酶酪胺和苯乙胺肝中MAO清除肠菌肝功能血浓度脑组织羟化酶苯乙醇胺羟苯乙胺拟去甲肾上腺素等递质神经传导障碍肝昏迷左旋多巴去甲肾上腺素改善神经传导脑内转变44【Pharmacokinetics】1.Absorptionoral,absorbedbysmallintestine,t1/21-3hBioavailabilityisaffectedbygastricemptying,gastricacidpH45

【Pharmacokinetics】2.DistributionandmetabolismLevodopaCOMTreuptakeMAOMAO:单胺氧化酶COMT:儿茶酚胺-O-甲基转移酶3.Elimination:kidney—46【Adversereactions】1.earlyreactions：(1)Gastrointestinaleffect:80%anorexia(厌食),nausea,vomitingtoleranceafterseveralweeks

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

【Adversereactions】2.long-termreactions(1)Hyperkinesia(运动过多症,

dyskinesia,运动障碍):90%(＞2years)

hand,feet,body—abnormalchoreoathetoidmovements

(舞蹈样手足徐动症)overstimulationofDA-Rinvoluntarymovement(不自主运动)orofacial(triad)

:sucking,lickingthetongue,chewingDA-Rblocker48(2)Fluctuationsinresponse(症状波动):

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

(左旋多巴的增效药）AADC(氨基酸脱羧酶)inhibitors

cabidopa,benserazide

(苄丝肼)

(2)MAO-Binhibitors

selegiline

(司来吉兰)(3)COMTinhibitors

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

notpenetrateBBB,onlyinhibitperipheryAADC,

increaseL-dopaintothebrain,reducethedosageofL-dopaby75%Benserazide(苄丝肼):

similar

CompoundPreparationsSinemet(息宁，心宁美)

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(司来吉兰)hypertensivecrisisMAO-B:CNS(nigrostriatal)selegiline(司来吉兰):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(溴隐亭):

D2agonism,D1partialantagonismPramipexole(普拉克索):D2agonism

Ropinirole(罗平尼咯):D2agonism

Lisuride(利修来得):D2agonism,D1weakantagonism3.DAreceptoragonists62

Bromocriptine

(溴隐亭)1.Smalldose:stimulateD2-likeRintuberoinfundibular（结节漏斗部）

reduceprolactin(PRL)andGHrelease2.Largedose:stimulateD2-likeRinsubstantia

nigro-striatal

Uses:PD,hyperprolactinemia

(高催乳素血症)

acromegaly(肢端肥大症)634.DrugsenhancingDAreleaseAmantadine(金刚烷胺)Mechanism:

1.↑releaseDAfromdopamine