Institute of Pharmacology Motor systems II: The basal ganglia and Drugs used for the treatment of Parkinson’s disease Zhang Bin（张斌） Institute of Pharmacology School of Medicine Shandong University

1. Components of Basal Ganglia neostriatum striatum (paleostriatum)

1. Caudate Nucleus (尾状核） 2. Putamen (壳核,豆状核壳） 3.Globus Pallidus (GP) （苍白球，旧纹状体） 4. Substantia Nigra (SN)（黑质） Pars Compacta (p.c.) (致密部） Pars Reticulata (p.r.) （网状部） 5. Subthalamic Nucleus (STN) (丘脑底核） 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) 1) MSN is the main efferent neurons in neostriatum 2) MSN（ Dendrites）接受的afferent神经: 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

4) Two types of DA receptors on MSN: D1 and D2-R D1-R : enhance direct pathway → Gpi (苍白球内侧部) D2-R : inhibit indirect pathway → GPe (苍白球外侧部)

3. Circuit related with Basal ganglia’s function in control of movement

1) direct pathway (直接通路): 当新纹状体活动↑→皮层运动前区活动↑ 2) indirect pathway (间接通路): 当新纹状体活动↑→皮层运动前区活动↓。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-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受体抑制间接通路

4. Diseases related with dysfunction of Basal ganglia Huntington’s disease (Chorea) 运动过多，肌张力降低 Parkinson disease 运动减少，肌张力增高

Parkinson’s Disease

CNS degenerative disease Alzheimer’s disease (AD,阿尔茨海默病) Parkinson’s disease (PD,帕金森病) Huntington disease (HD,亨廷顿病) Amyotrophic lateral sclerosis (ALS, 肌萎缩侧索硬化症)

Parkinson’s Disease Michael·J·Fox Katharine Hepburn Muhammad Ali in Alanta Olympic Katharine Hepburn Michael·J·Fox

Parkinson’s Disease - History First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.” “paralysis agitans” (震颤麻痹) James C. Parkinson

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黑质 1960: 发现与黑质纹状体中DA含量显著降低有关 世界帕金森病日 每年的4月11日——

Parkinson’s Disease - Symptoms 1. Resting tremor (静止震颤) 2. Bradykinesia (运动迟缓) 3. Rigidity (肌肉强直) Cogwheel phenomenon (Lead pipe phenomenon) 4. Ataxia (共济失调) 颤，慢，硬，共济失调

5. Others Abnormality of posture and gait Handwriting Memory impairment, confusion (精神混乱), disorientation Cognitive deficits Depression

Cogwheel phenomenon:

Early nonmotor symptoms PD symptoms Onset Diagnosis Dopaminergic neuron loss in PD Nonmotor % Remaining Dopaminergic Neurons Motor Sleep Olfactory* Mood Autonomic system Dopamine neurons account for less than 1% of brain neurons yet have a profound effect on function. This figure graphically demonstrates the decline in brain neurons that occurs in PD, and the progression from presymptomatic through the early nonmotor phases, then to the motor phase of PD, over time.1,2 The light blue line shows that, following the presymptomatic phase, nonmotor symptoms appear, and their occurrence increases over time until they plateau and continue throughout the disease. As the loss of dopaminergic neurons (red line) continues, the onset of additional nonmotor and motor symptoms continues.2 Dopaminergic neurons are lost rapidly in the early stages of PD (red line),2 but the typical motor symptoms do not emerge until 60% to 70% of neurons have degenerated.3 REFERENCES: 1. Halperin I, Morelli M, Korczyn AD, Youdim MB, Mandel SA. Biomarkers for evaluation of clinical efficacy of multipotential neuroprotective drugs for Alzheimer's and Parkinson's diseases. Neurotherapeutics. 2009;6:128-140. 2. Lang AE. The progression of Parkinson disease: a hypothesis. Neurology. 2007;68:948-952. 3. Schapira AH. Treatment options in the modern management of Parkinson disease. Arch Neurol. 2007;64:1083-1088. Presymptomatic phase Early nonmotor symptoms Specific symptoms Time (years) *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. Adapted 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 drugs for Alzheimer's and Parkinson's diseases, pages 128-140, Copyright 2009, with permission from Elsevier. 09228901/091244 19

PD - 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 old

PD - Etiology Unknown Increasing age (rare in those < 50; early or young onset) More often to occur in families with relatives with PD Environmental factors (pesticides, rural residence) Head trauma, Infection Caffeine and smoking have been found to be protective

Risk of Parkinson’s Disease Increased risk Age High Body Mass Index Male gender Family history Depression Environment factors rural living well-water drinking welding （焊接） head injury Decreased risk Caffeine intake Smoking cigarettes Anti-oxidants in diet (如类黄酮) Welding:焊接 Risk of Parkinson’s Disease

PD - Classification 1.Primary PD：unknown 2.Secondary: Parkinsonism Cerebral arteriosclerosis Encephalitis(脑炎) Drug poison: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

PD- Pathophysiology (1) 1. Dopamine (DA) theory 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 tension

Normal PD substantia nigra 正常人中脑有一条狭长的黑色素沉着部位，那便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，这是黑质神经元减少的缘故. 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.

Dopamine theory 黑质 DA 纹状体 DA Ach (＋) (—) GABA 脊髓前角运动神经元 调节运动功能

PD- Pathophysiology (2) 2. Oxidative stress - free radical theory Fe2+ DA氧化代谢 H2O2、O2- · ·OH 黑质 ComplexⅠ 抗氧化物（谷胱甘肽） 促进神经膜类脂氧化 破坏DA神经细胞膜功能 抗氧化治疗(MAO-BI, Vit E): 早期PD首选治疗方案。尽量延缓使用L-DOPA。是PD治疗较大的进展和传统观念的转变

PD - Animal model MPTP 6-OHDA Rotenone Paraquat

PD - Treatment No cure for PD Dopaminergic medication Non-dopaminergic medication Other strategies Surgical intervention (外科手术) Regular exercise (定期训练)

Dopaminomimetic Drugs Central Anticholinergic Drugs Antiparkinsonism drugs Dopaminomimetic Drugs DA Central Anticholinergic Drugs Ach

TH:酪氨酸羟化酶 AADC:L-芳香族氨基酸脱羧酶 TH AADC

Ⅰ Dopaminomimetic Drugs 1. Precursor of DA 2. Synergetic agents of L-dopa 　(左旋多巴的增效药） 3. DA receptor agonists 4. Drugs enhancing DA release

1. Precursor of DA levodopa（L-dopa, 左旋多巴） Dopamine

【Pharmacological actions and mechanism】 Penetrate BBB into the brain Decarboxylated (脱羧) by AADC to DA Supply DA to striatum

1. Parkinson’s disease: symptomatic treatment 【Clinical use】 1. Parkinson’s disease: symptomatic treatment widely used for almost all types of PD patients (1) early stage: good and stable effect 80% can be significantly improved, of which 20% recoverd to the normal state (2) later stage: effect gradually decreased, little effect after 3-5 years 用药初期和用药后期疗效差距很大

Characteristics: (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), less effective for resting tremor, difficult to improve dementia (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) or benserazide(苄丝肼)

2. Hepatic coma (肝昏迷): symptomatic treatment false neurotransmitter theory (伪递质学说） Levodopa metabolized to noradrenaline (NA) to replace false neurotransmitter

食物中芳香族氨基酸 酪胺和苯乙胺 肠菌 肝功能 血浓度 脑组织 羟化酶 苯乙醇胺 羟苯乙胺(鱆胺) 神经传导障碍 肝昏迷 左旋多巴 脱羧酶 酪胺和苯乙胺 被肝中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(鱆胺) 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 作为伪递质取代去甲肾上腺素 肝功能正常

【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)

2. Distribution and metabolism — DA Peripheral COMT Levodopa AADC reuptake MAO COMT 3. Elimination: kidney MAO:单胺氧化酶 COMT:儿茶酚胺-O-甲基转移酶

(1) Gastrointestinal effect: 80% (2) Cardiovascular effects: 【Adverse reactions】 1. early reactions： (1) Gastrointestinal effect: 80% anorexia(厌食), nausea, vomiting tolerance after several weeks domperidone(多潘立酮) 外周D2-R blocker (2) Cardiovascular effects: orthostatic hypotension 30% arrhythmias

【Adverse reactions】 2. long-term reactions (1) Hyperkinesia (运动过多症, dyskinesia,运动障碍): 50%(2-4m), 90% (＞2 years) involuntary movement (不随意运动) orofacial (triad) : sucking, licking the tongue, chewing hand, feet, body — abnormal choreoathetoid movements (舞蹈手足徐动症) over stimulation of DA-R DA-R blocker

(2) Fluctuations in response (症状波动): 40%-80% (3-5 years) DA-R agonist on-off phenomena MAOI inhibitor ivd, frequency (3) Psychic disorders Clozapine (氯氮平)： D4

【Drug interactions】 VitB6: coenzyme of AADC,  the activity of AADC Antipsychotic drugs: block DA-R of Nigro-striatal system, weaken L-DOPA function

2. Synergetic agents of L-dopa (左旋多巴的增效药） AADC (芳香氨基酸脱羧酶) inhibitors cabidopa, benserazide (苄丝肼) (2) MAO-B inhibitors selegiline (司来吉兰) (3) COMT inhibitors nitecapone (硝替卡朋）

DA Metabolism of L-dopa AADC DA reuptake L-DOPA AADC L-DOPA MAO-B COMT 3-OMD 3-OMD degradation ( 3-O-甲基多巴) compete Carrier BBB Brain Periphery

(1) AADC inhibitors (≠BBB) X AADC DA reuptake L-DOPA AADC L-DOPA DA MAO-B COMT COMT 3-OMD 3-OMD degradation ( 3-O-甲基多巴) compete Carrier BBB Brain Periphery

not penetrate BBB, only inhibit periphery AADC, Carbidopa (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 (苄丝肼): similar Compound Preparations Sinemet (息宁，心宁美) Levodopa : Carbidopa (10:1) Madopar (美多巴) Levodopa : Benserazide (4:1)

(2) MAO-B inhibitors (＝BBB) AADC DA reuptake L-DOPA AADC L-DOPA DA X MAO-B COMT COMT 3-OMD 3-OMD degradation ( 3-O-甲基多巴) compete Carrier BBB Brain Periphery

Selegiline (司来吉兰) BBB permeable, inhibit MAO-B: CNS reduce L-dopa dose and “on-off phenomena” low dose (＜10mg/d) —only inhibit MAO-B→DA↑ high dose (＞10mg/d)—inhibit MAO-A, too→ hypertensive crisis antioxidant effect

(3) COMT inhibitors (≠or＝ BBB) AADC DA reuptake L-DOPA AADC L-DOPA DA X X MAO-B COMT COMT 3-OMD 3-OMD degradation ( 3-O-甲基多巴) compete Carrier BBB Brain Periphery

CNS: DA degradation↓→ DA in CNS↑ Periphery: CNS: DA degradation↓→ DA in CNS↑ L-DOPA degradation↓ 3-OMD (3-O-甲基多巴)↓ carrier available for L-DOPA↑ L-DOPA that reach the brain↑ nitecapone (硝替卡朋): periphery Entacapone(恩他卡朋): periphery Tocapone(托卡朋): periphery and CNS

3. DA receptor agonists Dopamine receptors five main subtypes: D1 ~D5 D1-like receptors: D1, D5 D2-like receptors: D2, D3, D4 Nigro-striatal system: 激活D1-like receptor (D1,D5): 兴奋 激活D2-like receptor (D2, D3): 抑制

Less dyskinesia and on-off phenomenon Important in first line therapy Bromocriptine (溴隐亭): D2 agonism , D1 partial antagonism Pramipexole (普拉克索，森福罗 ): D2 agonism Ropinirole (罗平尼咯): D2 agonism Lisuride (利修来得): D2 agonism, D1 weak antagonism Less dyskinesia and on-off phenomenon Important in first line therapy

Bromocriptine (溴隐亭) 1. Small dose: stimulate D2-like R in tuberoinfundibular 　　　　　　　　　　　　　（结节漏斗部）  prolactin (PRL) and GH release 2. Large dose: stimulate D2-like R in substantia nigro-striatal Uses: PD, hyperprolactinemia (高催乳素血症) acromegaly (肢端肥大症)

4. Drugs enhancing DA release Amantadine (金刚烷胺) Mechanism: 1.↑release DA from dopaminergic terminals. 2.↓reuptake of DA. 3. dopamine receptor agonism Characteristics: 1. effect < L-dopa but >anticholinergic agents. 2. rapid onset, synergistic action with L-dopa

Ⅱ Central Anticholinergic Drugs

Benzhexol (苯海索, artane, 安坦) Not very strong Benzhexol (苯海索, artane, 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 phenothiazines

TH:酪氨酸羟化酶 AADC:L-芳香族氨基酸脱羧酶 TH AADC

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