《治疗帕金森病的药物课件》由会员分享，可在线阅读，更多相关《治疗帕金森病的药物课件（63页珍藏版）》请在金锄头文库上搜索。
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新纹状体新纹状体新纹状体新纹状体新纹状体新纹状体是基底节的核心，许多神经传入进来，也会是基底节的核心，许多神经传入进来，也会是基底节的核心，许多神经传入进来，也会是基底节的核心，许多神经传入进来，也会发出神经纤维到其他部位，构成回路调控躯体运动发出神经纤维到其他部位，构成回路调控躯体运动发出神经
3、纤维到其他部位，构成回路调控躯体运动发出神经纤维到其他部位，构成回路调控躯体运动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:Glu neurons in cortex DA neurons in SNc Ach neurons in striatum GABA neurons in striatum 3)MSN axons compose efferent sy
4、stem,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)673.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
5、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 gangliaHunt
6、ingtons disease(Chorea)运运动过动过多，肌多，肌张张力降低力降低Parkinson disease 运运动动减少，肌减少，肌张张力增高力增高1011Parkinsons Disease12 CNS degenerative diseaseAlzheimers disease (AD,阿尔茨海默病阿尔茨海默病)Parkinsons 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)Muhammad Ali in Alan
7、ta OlympicMuhammad Ali in Alanta OlympicMuhammad Ali in Alanta OlympicMuhammad Ali in Alanta OlympicParkinsons DiseaseKatharine Hepburn MichaelJFox 14First 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-His
8、tory James C.Parkinson15The 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.Bradykines
9、ia(运动迟运动迟缓缓)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175.Others Abnormality of posture and gaitHandwriting Memory impairment,confusion(精神混乱精神混乱),disorientationCognitive deficitsDepression18Presymptomatic phaseOnsetSleepOlfactory*MoodAutonomic
10、 systemDiagnosisEarly nonmotor symptomsSpecific symptomsMotorPD symptoms Dopaminergic neuron loss in PD%Remaining%Remaining Dopaminergic NeuronsDopaminergic NeuronsTime(years)NonmotorAdapted image reprinted from Neurotherapeutics,Vol.6,Halperin I,Morelli M,Korczyn AD,Youdim MB,Mandel SA.Biomarkers f
11、or evaluation of clinical efficacy of multipotential neuroprotective drugs 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.Neurolo
12、gy.2007;68:948-952.Ross et al.Ann Neurol.2008;63:167-173.20PD-Epidemiology 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;ea
13、rly or young onset)More often to occur in families with relatives with PDEnvironmental factors(pesticides,rural residence)Head trauma,InfectionCaffeine and smoking have been found to be protective22Risk of Parkinsons DiseaseIncreased riskAgeHigh Body Mass IndexMale genderFamily historyDepressionEnvi
14、ronment factorsrural livingwell-water drinkingwelding（焊接）head injuryDecreased riskCaffeine intakeSmoking cigarettesAnti-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Ch
15、emicals:Mn2+、除草剂、杀虫剂等除草剂、杀虫剂等241.Dopamine(DA)theory PD-Pathophysiology(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
16、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首选首选治疗方案。尽量延缓使用治疗方案。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转变28PD-Animal modelMPTP6-OHDARotenoneParaquat29PD-TreatmentNo cure for PDDopaminergic medicationNon-dopaminergic medicationOther strategi
