1、1Motor systems II:The basal ganglia and Drugsused for the treatment of Parkinsons diseaseZhang Bin（张斌）（张斌）Institute of PharmacologySchool of MedicineShandong University1.Components of Basal Ganglia3neostriatumstriatum(paleostriatum)1.Caudate Nucleus(尾状核）尾状核）2.Putamen(壳核壳核,豆状核壳）豆状核壳）3.Globus Pallidus
2、(GP)（苍白球，旧纹状体）（苍白球，旧纹状体）4.Substantia Nigra(SN)（黑质）（黑质）Pars Compacta (p.c.)(致密部）致密部）Pars Reticulata(p.r.)（网状部）（网状部）5.Subthalamic Nucleus(STN)(丘脑底核）丘脑底核）4新纹状体新纹状体2.Medium spiny neuron in striatum (MSN,中型多棘神经元中型多棘神经元)1)MSN is the main efferent neurons in neostriatum 2)MSN（Dendrites）接受）接受的的afferent神经神经:
3、Glu neurons in cortex DA neurons in SNc Ach neurons in striatum GABA neurons in striatum 3)MSN axons compose efferent system,with GABA as the neurotransmitter 54)Two types of DA receptors on MSN:D1 and D2-R D1-R:enhance direct pathway Gpi(苍白球内侧部苍白球内侧部)D2-R:inhibit indirect pathway GPe(苍白球外侧部苍白球外侧部)6
4、73.Circuit related with Basal ganglias function in control of movement 81)direct pathway(直接通路直接通路):当新纹状体活动当新纹状体活动皮层运皮层运动前区活动动前区活动2)indirect pathway(间接通路间接通路):当新纹状体活动当新纹状体活动皮层运皮层运动前区活动动前区活动。此通路部分抵消直接通路对皮层的兴奋作用。此通路部分抵消直接通路对皮层的兴奋作用3)Substantia nigra-Neostriatum pathway(黑质黑质-新新 纹状纹状体通路体通路):此通路对上述两通路起调控作
5、用此通路对上述两通路起调控作用DA通过通过D1受体增强直接通路，通过受体增强直接通路，通过D2受体抑制间接通路受体抑制间接通路94.Diseases related with dysfunction of Basal ganglia Huntingtons disease(Chorea)运动过多，肌张力降低运动过多，肌张力降低 Parkinson disease 运动减少，肌张力增高运动减少，肌张力增高1011Parkinsons Disease12 CNS degenerative disease Alzheimers disease (AD,阿尔茨海默病阿尔茨海默病)Parkinsons
6、disease(PD,帕金森病帕金森病)Huntington disease (HD,亨廷顿病亨廷顿病)Amyotrophic lateral sclerosis(ALS,肌萎缩侧索硬化症肌萎缩侧索硬化症)Katharine Hepburn MichaelJFox 14 First described in 1817 by an English physician,James Parkinson,in “An Essay on the Shaking Palsy.”“paralysis agitans”(震颤麻痹震颤麻痹)Parkinsons Disease-History James C.P
7、arkinson15 The famous French neurologist,Charcot,further described the syndrome in 1868 (rigidity)-named”Parkinson disease”.1919:确定病变部位主要在确定病变部位主要在黑质黑质 1960:发现与黑质纹状体中发现与黑质纹状体中DA含量显著降低含量显著降低有关有关世界帕金森病日世界帕金森病日每年的每年的4月月11日日16 Parkinsons Disease-Symptoms1.Resting tremor(静止震静止震颤颤)2.Bradykinesia(运动迟运动迟缓缓)
8、3.Rigidity(肌肉强肌肉强直直)Cogwheel phenomenon(Lead pipe phenomenon)4.Ataxia(共济失调共济失调)颤，慢，硬，共济失调颤，慢，硬，共济失调17 5.Others Abnormality of posture and gaitHandwriting Memory impairment,confusion(精神混乱精神混乱),disorientationCognitive deficitsDepression18Presymptomatic phaseOnsetSleepOlfactory*MoodAutonomic systemDiag
9、nosisEarly nonmotor symptomsSpecific symptomsMotorPD symptoms Dopaminergic neuron loss in PDTime(years)NonmotorAdapted image reprinted from Neurotherapeutics,Vol.6,Halperin I,Morelli M,Korczyn AD,Youdim MB,Mandel SA.Biomarkers for evaluation of clinical efficacy of multipotential neuroprotective dru
10、gs for Alzheimers and Parkinsons diseases,pages 128-140,Copyright 2009,with permission from Elsevier.*Olfactory dysfunction may predate clinical PD by at least 4 years.Halperin et al.Neurotherapeutics.2009;6:128-140.Lang.Neurology.2007;68:948-952.Ross et al.Ann Neurol.2008;63:167-173.20PD-Epidemiolo
11、gy The second most common neurodegenerative disorder after AD.Increase with age population 65 years old:1%mean age at onset:60 years old 85%of patients are over 65 years old21PD-EtiologyUnknown Increasing age(rare in those 50;early or young onset)More often to occur in families with relatives with P
12、DEnvironmental factors(pesticides,rural residence)Head trauma,InfectionCaffeine and smoking have been found to be protective22Risk of Parkinsons DiseaseIncreased risk Age High Body Mass Index Male gender Family history Depression Environment factorsrural livingwell-water drinkingwelding（焊接）head inju
13、ryDecreased risk Caffeine intake Smoking cigarettes Anti-oxidants in diet(如类黄酮)23 PD-Classification1.Primary PD：unknown2.Secondary:ParkinsonismCerebral arteriosclerosis Encephalitis(脑炎脑炎)Drug poison:氰化物、利舍平、吩噻嗪类抗精神病药等氰化物、利舍平、吩噻嗪类抗精神病药等Chemicals:Mn2+、除草剂、杀虫剂等除草剂、杀虫剂等241.Dopamine(DA)theory PD-Pathophy
14、siology(1)DA neuronal degeneration in substantia nigra reduced or lack of dopamine in the striatum function of DA in nigro-striatal DA pathway the function of Ach muscular tension25NormalPDsubstantia nigra正常人中脑有一条狭长的黑色素沉着部位，是正常数量的黑质神经元聚集的部位。而在帕金森病人中脑的相应部位则颜色浅淡，是黑质神经元减少的缘故.26Dopamine theoryAch黑质黑质纹状体
15、纹状体DADA()()调节运动功能调节运动功能脊髓前角运动神经元脊髓前角运动神经元GABA27DA氧化代谢氧化代谢H2O2、O2-OH Fe2+促进神经膜类脂氧化促进神经膜类脂氧化破坏破坏DA神经细胞膜功能神经细胞膜功能 Complex 抗氧化物（谷胱甘肽）抗氧化物（谷胱甘肽）黑质黑质2.Oxidative stress-free radical theory PD-Pathophysiology(2)抗氧化治疗抗氧化治疗(MAO-BI,Vit E):早期早期PD首首选治疗方案。尽量延缓使用选治疗方案。尽量延缓使用L-DOPA。是。是PD治疗较大的进展和传统观念的转变治疗较大的进展和传统观念的
16、转变28PD-Animal model MPTP 6-OHDA Rotenone Paraquat29PD-TreatmentNo cure for PD Dopaminergic medication Non-dopaminergic medication Other strategiesSurgical intervention(外科手术)Regular exercise(定期训练)30Antiparkinsonism drugsDAAchDopaminomimetic DrugsCentral Anticholinergic Drugs31AADCTH:酪氨酸羟化酶酪氨酸羟化酶THAAD
17、C:L-芳香族氨基酸脱羧酶芳香族氨基酸脱羧酶32 Dopaminomimetic Drugs 1.Precursor of DA 2.Synergetic agents of L-dopa(左旋多巴的增效药）左旋多巴的增效药）3.DA receptor agonists 4.Drugs enhancing DA release33 1.Precursor of DA levodopa（L-dopa,左旋多巴）左旋多巴）LevodopaDopamine34【Pharmacological actions and mechanism】Penetrate BBB into the brain Dec
18、arboxylated(脱羧脱羧)by AADC to DA Supply DA to striatum 35【Clinical use】widely used for almost all types of PD patients 1.Parkinsons disease:symptomatic treatment(1)early stage:good and stable effect 80%can be significantly improved,of which 20%recoverd to the normal state(2)later stage:effect graduall
19、y decreased,little effect after 3-5 years用药初期和用药后期疗效差距很用药初期和用药后期疗效差距很大大36Characteristics:(1)have good effect on mild and younger patients,less effect on severe and elderly patients(2)more effective for muscular rigidity and akinesia(运动不能运动不能),less effective for resting tremor,difficult to improve de
20、mentia(3)slow onset,initial effective time is 2-3 w,1-6 m to Emax(4)not effective for Parkinsonism caused by phenothiazines antipsychotic drugs(5)drug combination:combined with peripheral AADC inhibitor,reduce the dosage of L-DOPA by 75%.Cabidopa(卡比多巴卡比多巴)or benserazide(苄丝肼苄丝肼)372.Hepatic coma(肝昏迷肝昏
21、迷):symptomatic treatmentfalse neurotransmitter theory(伪递质学说）伪递质学说）Levodopa metabolized to noradrenaline(NA)to replace false neurotransmitter38食物中芳香族氨基酸食物中芳香族氨基酸脱羧酶脱羧酶酪胺和苯乙胺酪胺和苯乙胺被肝中MAO清除肠肠菌菌肝功能肝功能血浓度血浓度脑组织脑组织羟化酶羟化酶苯乙醇胺苯乙醇胺羟苯乙胺羟苯乙胺(鱆胺鱆胺)神经传导障碍神经传导障碍肝昏迷肝昏迷左旋多巴左旋多巴去甲肾上腺素去甲肾上腺素改善神经传导改善神经传导脑内脑内转变转变作为伪递质取
22、代作为伪递质取代去甲肾上腺素去甲肾上腺素肝功能正常肝功能正常39 【Pharmacokinetics】1.Absorption oral,absorbed by small intestine,t1/2 1-3h Bioavailability is affected by gastric emptying,gastric acid pH(delay of empty and low PH can decrease bioavailability)402.Distribution and metabolismLevodopaCOMTreuptakeMAOMAO:单胺氧化酶单胺氧化酶COMT:儿
23、茶酚胺儿茶酚胺-O-甲基转移酶甲基转移酶3.Elimination:kidneyAADCPeripheral COMTDA41 【Adverse reactions】1.early reactions：(1)Gastrointestinal effect:80%anorexia(厌食厌食),nausea,vomiting tolerance after several weeks domperidone(多潘立酮多潘立酮)外周外周D2-R blocker(2)Cardiovascular effects:orthostatic hypotension 30%arrhythmias42 【Adv
24、erse reactions】2.long-term reactions(1)Hyperkinesia(运动过多症运动过多症,dyskinesia,运动障碍运动障碍):50%(2-4m),90%(2 years)hand,feet,body abnormal choreoathetoid movements (舞蹈手足徐动症舞蹈手足徐动症)involuntary movement(不随意运动不随意运动)orofacial(triad):sucking,licking the tongue,chewingDA-R blockerover stimulation of DA-R43(2)Fluct
25、uations in response(症状波动症状波动):on-off phenomena 40%-80%(3-5 years)(3)Psychic disorders Clozapine(氯氮平氯氮平)：D4MAOI inhibitorDA-R agonistivd,frequency 44 【Drug interactions】VitB6:coenzyme of AADC,the activity of AADCAntipsychotic drugs:block DA-R of Nigro-striatal system,weaken L-DOPA function 452.Synerg
26、etic agents of L-dopa(左旋多巴的增效药）左旋多巴的增效药）(1)AADC(芳香氨基酸脱羧酶芳香氨基酸脱羧酶)inhibitors cabidopa,benserazide(苄丝肼苄丝肼)(2)MAO-B inhibitors selegiline(司来吉兰司来吉兰)(3)COMT inhibitors nitecapone(硝替卡朋）硝替卡朋）46Metabolism of L-dopaL-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴甲基多巴)BBBBrainPeriph
27、erycompete CarrierX47(1)AADC inhibitors(BBB)L-DOPADAAADCCOMT3-OMDL-DOPAcompete Carrier3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴甲基多巴)BBBBrainPeriphery48Carbidopa(卡比多巴卡比多巴):not penetrate BBB,only inhibit periphery AADC,increase L-dopa into the brain,reduce the dosage of L-dopa by 75%Benserazide
28、(苄丝肼苄丝肼):similar Compound PreparationsSinemet(息宁，心宁美息宁，心宁美)Levodopa:Carbidopa(10:1)Madopar(美多巴美多巴)Levodopa:Benserazide(4:1)49(2)MAO-B inhibitors(BBB)L-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCXdegradationMAO-BCOMTreuptake(3-O-甲基多巴甲基多巴)BBBBrainPeripherycompete Carrier50Selegiline(司来吉兰司来吉兰)BBB permeable,in
29、hibit MAO-B:CNS reduce L-dopa dose and“on-off phenomena”low dose(10mg/d)only inhibit MAO-BDA high dose(10mg/d)inhibit MAO-A,too hypertensive crisis antioxidant effect51X53(3)COMT inhibitors(or BBB)L-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCXdegradationMAO-BCOMTreuptake(3-O-甲基多巴甲基多巴)BBBBrainPeripherycompe
30、te Carrier54 Periphery:CNS:DA degradation DA in CNSL-DOPA degradation3-OMD(3-O-甲基多巴甲基多巴)carrier available for L-DOPAL-DOPA that reach the brainnitecapone(硝替卡朋硝替卡朋):peripheryEntacapone(恩他卡朋恩他卡朋):peripheryTocapone(托卡朋托卡朋):periphery and CNS55Dopamine receptorsfive main subtypes:D1 D5 D1-like receptors:
31、D1,D5 D2-like receptors:D2,D3,D43.DA receptor agonists Nigro-striatal system:激活激活D1-like receptor(D1,D5):兴奋兴奋激活激活D2-like receptor(D2,D3):抑制抑制56Bromocriptine(溴隐亭溴隐亭):D2 agonism,D1 partial antagonismPramipexole(普拉克索，森福罗普拉克索，森福罗):D2 agonism Ropinirole(罗平尼咯罗平尼咯):D2 agonism Lisuride(利修来得利修来得):D2 agonism,
32、D1 weak antagonismLess dyskinesia and on-off phenomenonImportant in first line therapy57 Bromocriptine(溴隐亭溴隐亭)1.Small dose:stimulate D2-like R in tuberoinfundibular（结节漏斗部）（结节漏斗部）prolactin(PRL)and GH release 2.Large dose:stimulate D2-like R in substantia nigro-striatal Uses:PD,hyperprolactinemia(高催乳素
33、血症高催乳素血症)acromegaly(肢端肥大症肢端肥大症)584.Drugs enhancing DA releaseAmantadine(金刚烷胺金刚烷胺)Mechanism:1.release DA from dopaminergic terminals.2.reuptake of DA.3.dopamine receptor agonism Characteristics:1.effect anticholinergic agents.2.rapid onset,synergistic action with L-dopa59 Central Anticholinergic Drugs60 Benzhexol(苯海索苯海索,artane,安坦安坦)Blocking the M-R,cholinergic function in the nigrostriatal.Improve the tremor of PD,little effect on bradykinesia and rigidity Effective for Parkinsonism caused by phenothiazinesNot very strong61AADCTH:酪氨酸羟化酶酪氨酸羟化酶THAADC:L-芳香族氨基酸脱羧酶芳香族氨基酸脱羧酶62Thank you!Thank you!63
