高级病生第9次课神经系统疾病信号转导机制选修课.ppt

神经系统疾病信号转导机制,Zhang Lu,Department of PathophysiologySouthern Medical University,Guangzhou,一、脑的神经解剖学特点二、神经元结构与信息传递三、阿尔茨海默病四、帕金森病 五、药物成瘾,Organization of theNervous System Central Nervous System（中枢神经系统）-Brain and spinal cord(脑和脊髓）Peripheral Nervous System（周围神经系统）-everything else!-cranial nerves(12)（脑神经）-spinal nerves(31)（脊神经）,一、脑的神经解剖学特点,Central Nervous SystemPeripheral Nervous System,Brain,Spinal Cord,Cranial Nerves,Spinal Nerves,Peripheral Ganglia,Division of the nervous system,Central Nervous System(CNS),7 Main Parts of the CNS Spinal Cord Medulla oblongata Pons Cerebellum Midbrain Diencephalon Cerebrum,The Brains Vital Statistics Adult weight:about 3 pounds Adult size:a medium cauliflower Number of neurons:100,000,000,000(100 billion)Number of synapses(the gap between neurons):100,000,000,000,000(100 trillion),Human Brain,Directions in the nervous system-Axes,Orientation Axes in the brainRostral-Caudal(front-back)anterior-posteriorDorsal-Ventral(up down)Lateral-Medial(sideways mid),Directions in the nervous system-Planes,From macro-to microanatomy,Difference of white“-and grey“matterGrey matter:nerve cell bodiesWhite matter:nerve fibres,Coronal section of a macaque brain,二、神经元结构与信息传递 具有极性和高度特化 具有对化学刺激整合的能力 电信号可沿轴突传递至递质分泌点,胞体,树突,轴突,终末,Histological organization of grey matter,The cortex is arranged out of 6 histological layers which have distinct processing and input-/output functions,Function of different layers,Neurons in different layers have distinct projection characteristics,Microanatomy,The brain consists of about 100 billion cells.,Nerve cells(neurons),Glia(glial cells),processing units,Control of environment of neurons,Nerve cells(neurons),Sketch of a neuron,Nucleus,Dendrites,Dendrites,Myelin,Axons,Dendrites-Input Cell body(soma)Integration;protein production,genes,energy production Axon-Output,Structure of neurons-Dendrites,At dendrites,the neurons recieve input via axons of other neurons at synapses,dendritic spine,Structure of neurons-Soma,In the soma of the cells,the cell nucleus is located(containing the DNA,i.e.genetic code);the synthesis of the proteins(within ribosomes and endoplasmatic reticulum)as well as energy production(mitochondria)are performed.,Glial cells,astrocytes,oligodendrocytes,Astrocytes,Astrocytes connect the extraneuronal space with the blood vessels,Oligodendrocytes,Oligodendrocytes sheat the axons of the neurons to increase conductance of action potential,Presynaptic vesicles with neurotransmitter,Released transmitter,Transmitter binds to receptor,Na+,Transmitter-Resorption from synaptic cleft,Synapse Communication between neurons,化学性突触的超微结构,突触(synapse)两个神经元间的接触点 特化的细胞连接 功能接触，无原生质相通 分为两类 化学性突触(单向性)电突触(双向性)神经元间的信息传递,神经递质,神经递质和内源性活性物质的研究概况,1904，Elliott，冲动传导到交感神经末梢，可能从那里释放肾上腺素，在作用于效应器细胞。1921，Loewi,通过蛙心灌流发现“迷走素”Dale，发现神经肌肉接头处的神经递质是ACH。Loewi,Dale共享1936年诺贝尔奖。1921，Cannon刺激交感神经后，从肝脏中分离出的物质命名为“交感素”；1949，这种物质被von Eulur鉴定为去甲肾上腺素，为此获1970年诺贝尔奖。1960-今，50多种神经肽被发现。1980-1988，FurchgottIgnarroMoncade三个研究小组相继发现NO为神经递质,三人共享1998年诺贝尔奖。,鉴定递质的主要条件,存在：在突触前神经元内有该物质及其合成酶的存在释放：从突触前末梢可释放足以在突触后细胞或效应器引起一定反应的物质。相同的突触后效应：将适当浓度的该物质人工地施加到突触后细胞上应能引起与由神经诱发的相同反应。灭活机制：应找到将该物质从突触间隙中除去的机制。,1、胆碱类 乙酰胆碱 Ach,Acetylcholine,2、单胺类 monoamines（1）儿茶酚胺catecholamine,CA 去甲肾上腺素 norepinephrine(noradrenaline)多巴胺 dopamine 肾上腺素 epinephrine(2)吲哚胺（indole amine,IA）5-羟色胺（5-hydroxytryptamine,5-HT,）3、氨基酸类amino acids 抑制性氨基酸类：-氨基丁酸，甘氨酸 兴奋性氨基酸类：谷氨酸，天冬氨酸4、多肽类，神经肽类 阿片肽，其他 神经肽,递质的类型,化学突触的信号转导,Receptors can be located postsynaptically,Receptors,Receptors can be located presynaptically,Ionotropic receptors Some receptors are ion channels and allow either+ions(Na+,K+,Ca2+)or ions(Cl-)to cross membrane,Some subunits activate K+channels Some subunits activate Na+channels or Ca2+channels Some subunits activate second messengers,metabotropic receptors(G protein-coupled),metabotropic receptors,Metabotropic receptors that are coupled to Gs proteins stimulate second messenger signaling,Metabotropic receptors that are coupled to Gi proteins inhibit second messenger signaling,Gs,Gi,Summary of types of receptorsIonotropic receptors:Ion channel in the membrane that forms a pore;ligands can bind either outside or inside the pore(but always outside the neuron).,Metabotropic receptors:Large protein in the membrane;ligand binds on the outside and activates G-protein intracellularly.,Excitatory neurotransmission,Glutamate：Glutamate is often considered the“excitatory neurotransmitter”in the brain,mGluR1,mGluR5,NMDA receptor,Gs,Glutamate,Inhibitory Neurotransmission,GABA：GABA is often considered the“inhibitory neurotransmitter”,GABA B receptor,GABA A receptor,Gi,GABA,Dopamine,Dopamine is considered a neuromodulator because it activates only metabotropic receptors and thus its signaling is relatively slow.,D1receptor,Gs,D2receptor,Gi,So dopamine can be stimulatory or inhibitory,depending upon which receptor it activates,Playing with receptors:agonists（激动剂）,Regardless of the type of receptor(ionotropic or metabotropic),any compound that binds to a receptor and stimulates receptor activity is called an agonist(激动剂）Neurotransmitters are all agonists at their receptorsCertain drugs are also agonists at neurotransmitter receptors,(Angel dust),NMDA receptor,Blocking the signal:antagonists（抑制剂）,Compounds that have affinity for a receptor but no efficacy are called antagonists（拮抗剂）,Antagonists:“receptor blockers”,Antagonists bind to the receptor but are not capable of activating them(i.e.,no efficacy);block the effects of an agonist,阿尔茨海默病 Alzheimers disease,变性性痴呆：阿尔茨海默病、帕金森病、肌萎缩侧索硬化、Pick病等血管性痴呆：多发性脑梗死、缺血缺氧性脑病、出血性痴呆等继发性痴呆：脑肿瘤、硬膜下血肿、脑脓肿、脑外伤、中毒、感染性疾病等,痴呆的类型与常见原因,AD的全球患病率,美国AD的发生最常见目前的病例：约有400万超过65岁以后每增加5岁患病率增加一倍超过85岁的人中几乎50都患有AD,AD的全球患病率,欧洲 目前在欧洲估计有550万人患有痴呆 发展中国家 目前全球有1800万人患有痴呆，其中 有66居住在发展中国家,阿 尔 茨 海 默(Alzheimer),1907年阿尔茨海默首次报告了一例具有进行性痴呆表现的51岁女性患者。当医生给她看一个物体时，她最初能够说出这个物体的正确名称，重复几次都是一样，但是以后突然间，她把一切都忘掉了。当阅读一本书时，她可能无缘无故地跳过一些句子，她也许会一个字母、一个字母地拼读每一个字，也许会读起来完全没有抑扬顿挫。在书写测验时，她会反复书写同一个音节，而完全忽略其他的音节，因而变得完全错乱，六神无主。当她讲话时，常常是使用杂乱无章的词句，应用似是而非的表达方式。有时，在说话时会突然停下来，一言不发。不能理解向她提出的任何问题。找不到回自己住处的路。病情逐渐恶化，四年半后死亡。患者死后病理检查显示：大脑皮层萎缩，神经原纤维缠结。其后，又有类似的病例报道。因其发病于老年前期，早期认为这是一种和老年性痴呆不同的疾病，于年把这种病命名为阿尔茨海默病。,Alzheimer Disease(AD),（一）基本概念 1、Alzheimer 病 临床表现上出现明显的记忆、认知、思维、情感及精神障碍以及性格改变等智能障碍（痴呆），病理学上以神经细胞内神经原纤维缠结和细胞外淀粉样物质沉淀为主要特征的神经变性疾病。2、痴呆 是指在意识清醒状态下，出现记忆、认知和思维功能缺损，或伴有语言、视空间技能、情感及人格障碍的获得性、持续性智能障碍综合症，是影响老年人健康和生活质量的常见病多发病。,（二）危险因素 1、老龄 2、基因异常 3、雌激素缺乏 4、头颅外伤史 5、性别,（三）Alzheimer病临床表现特征 1、记忆障碍 2、认知思维障碍 3、性格改变 4、情感及精神障碍,（四）Alzheimer病的发病机制 1、神经原纤维缠结：P-tau 2、脑内淀粉样物质沉淀：A淀粉肽 3、神经递质及其受体异常,Normal tau,AD p-tau,Ser Thr,p,p,p,p,p,p,p,p,ADP,ATP,p,p,Protein kinases?,Protein phosphatases,Imbalanced phosphorylation system leads to tau hyperphosphorylation,Ser Thr,Pi,神经原纤维缠结,tau 蛋白异常修饰的机制机器在痴呆发生中的作用,PHF,双螺旋丝；NFT，神经元纤维缠结；HMW-MAP，高分子量微管相关蛋白。,Beta-amyloid PlaquesAmyloid precursor protein(APP)is the precursor to amyloid plaque.1.APP sticks through the neuron membrane.2.Enzymes cut the APP into fragments of protein,including beta-amyloid.3.Beta-amyloid fragments come together in clumps to form plaques.,1.,2.,3.,In AD,many of these clumps form,disrupting the work of neurons.This affects the hippocampus and other areas of the cerebral cortex.,Slide 17,2、脑内淀粉样物质沉淀,脑内淀粉样物质沉淀：A淀粉肽A-淀粉肽前体蛋白基因 早老蛋白-1基因早老蛋白-2基因 A淀粉肽载脂蛋白E等位基因2巨球蛋白基因,A毒性与痴呆,Accumulation of tau and A in AD,Affected brain regions of AD,治 疗支持、对症治疗,帕金森病 Parkinsons disease,帕金森病(Parkinsons disease,PD)又名震颤麻痹(paralysis agitans)。本病由Parkinson(1817)首先描述。,Parkinsons disease,帕金森病的临床特点,静止性震颤运动迟缓肌强直姿势步态异常,流 行 病 学,60岁以上人群患病率为1000/10万，并随年龄增长而增高，两性分布差异不大一种常见的中老年人神经系统变性疾病,病 理,进行性黑质和蓝斑核含黑色素多巴胺神经元大量丧失(50%70%),病 理,胞浆内出现特征性嗜酸性包涵体-Lewy小体，a-突触核蛋白基因是Lewy小体中重要成分。类似改变也见于蓝斑、中缝核、迷走神经背核等，程度较轻,病理生理基础,黑质-纹状体多巴胺系统功能紊乱，多巴胺含量显著减少(80%99%)该生化异常与临床症状严重程度成正比,PD发病机制,PD建模,1,.,2,3,1,.,2,3,1,.,2,机制,比较,建模选择,6-OHDA建模机制 6-OHDA 是多巴胺的羟基化衍生物，高选择地引起交感神经肾上腺素能神经末梢急性溃变，竞争性抑制DA，阻滞线粒体呼吸链，氧化应激增强，多巴胺能神经元选择性缺失、-synuclein蛋白聚集、泛素水平增加,MPTP建模机制 MPTP 强脂溶性，易通过血脑屏障，选择性浓集于黑质，在单胺氧化酶B 作用下，转化为结构与DA类似但有毒性的1甲基4苯基吡啶离子（MPP），进入多巴胺能神经末梢和胞体，产生氧化应激损伤，导致多巴胺能神经元凋亡，嗜酸性内涵体及-synuclein 表达增加。,单胺氧化酶B(MAO-B),DAT,MPTP诱导PD机制,MPDP:1-甲基-4苯基-二氧吡啶，MPP+:MPDP:1-甲基-4苯基-吡啶离子，DAT：多巴胺转运体。,药 物 治 疗,恢复纹状体DA与ACh递质系统平衡。包括抗胆碱能药、多种改善DA递质功能药物药物治疗只能改善症状，不能阻止病情发展，需终生服用,帕金森病对症治疗：抗胆碱能药物,震颤明显、年龄较轻患者，震颤和强直有一定效果，运动迟缓疗效较差。安坦(artane)：12mg，3次/d口服副作用：口干、视物模糊、便秘和排尿困难，严重者幻觉、妄想青光眼及前列腺肥大患者禁用,帕金森病对症治疗：左旋多巴制剂,机制：补充外源性多巴胺前体“金标准”:左旋多巴合并多巴脱羧酶抑制剂是目前最有效的控制症状药物,帕金森病对症治疗：左旋多巴制剂,治疗原则从小剂量开始，缓慢递增剂量。剂量应个体化，根据患者年龄、症状类型、严重程度、就业情况、经济承受能力等选择药物饭前或后1小时服用,您将如何选择？,早还是晚使用左旋多巴？,并发症的出现,生活质量,左旋多巴与药物引起的并发症,药效,并发症,病程,5-10年,剂未现象,开关现象,异动症,僵住现象,DA储存,2.0,1.37,认知功能障碍,1.47,药物治疗并发症分类,运动症状波动(Motor Fluctuations)剂末效应(Wearing-off)：疗效减退“开-关”现象(On-off)：症状在突然缓解与加重中波动僵住(Freezing),药物治疗并发症分类,异动症(Dyskinesia)关期肌张力不全(Early-morning dystonia)峰期不自主舞蹈样运动(Peak-dose dyskinesia)剂初和剂末期异动症(Onset and end-of-dose dyskinesia),毒品成瘾(Drug addiction),加利福利亚罂粟花,毒品成瘾(drug addiction):指不择手段、不记后果地强制性地获取、使用某种毒品。,吸毒-全世界广泛关注的问题吸毒-我国日益严重的社会问题吸毒-广东省尤为突出的问题世界吸毒人数-超过2亿人，消耗1万亿美元我国登记在案吸毒人数-116万，2000亿人民币广东登记在册吸毒人员-19万人，40亿人民币,毒品的种类,镇静剂:海洛因,巴比土酸盐兴奋剂:可卡因,快克,安非他命致幻剂:大麻,摇头丸,麦角酰二乙胺,Dopamine Projection of dopaminergic neurons,Neuroanatomy,Nigrostriatal dopamine pathway(黑质纹状体多巴胺通路):Substabtia nigra(黑质)caudoputamen(尾壳核)Mesoaccumbens dopamine pathway(中脑边缘多巴胺通路):Ventral tegmental area(VTA)(腹侧背盖区)Nucleus accumbens(伏核)Mesocortical dopamine pathway(中脑皮质多巴胺通路):Ventral tegmental area(VTA)prefrontal cortex,Dopamine Receptor(多巴胺受体)Classification D1 class:D1,D5 receptor.Gs/GolfD2 class:D2,D3,D4 receptor.Gi/GoExpression D1 and D2:striatum(caudoputamen and nucleus accumbens),neocortex,amygdala D3:nucleus accumbens,olfactory tubercle,amygdala,ventral pallidumD4 and D5:Very low,Production of Dopamine,cocaine,Brain regions and neuronal pathways,Natural rewards,The reward pathway,基 本 特 性,Sensitization(敏化性):Enhanced drug responsiveness with repeated exposure to a constant doseTolerance(耐受性):Reduced drug responseness with repeated exposure to a constant doseDependance(依赖性):Altered physiological state that develop to compensate for persist drug exposure and that gives rise to a withdrawl syndrome after cessation of drug exposure.,The synapse and synaptic neurotransmission,Dopamine neurotransmission,Dopamine and the production of cyclic AMP,The action of heroin(morphine),Localization of opiate binding sites within the brain and spinal cord,Morphine binding within the reward pathway,Opiates binding to opiate receptors in the nucleus accumbens:increased dopamine release,Rats self-administer heroin,The action of cocaine,Localization of cocaine binding sites,Dopamine binding to receptors and uptake pumps in the nucleus accumbens;the action of cocaine,Cocaine dependence and activation of the reward pathway,Rats self-administer cocaine,Addictive drugs activate the reward system via increasing dopamine neurotransmission,Molecular Mechanisms of Addiction,1、Transcriptional mechanisms CREB and upregulation of cAMP,c-fos is a key molecular regulator of brain function,2、Post-transcriptional mechanism,3、Regulation of synaptic structure,Plasticity of the brain building of synapses,Neurotransmitter Control of Striatal IEG Expression,Molecular Mechanisms of Neuroadaptation,Thanks!,