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Motor systems II: The basal ganglia and Drugs

used for the treatment of Parkinson’s disease

Lou haiyanLou haiyan （娄海燕）（娄海燕）Institute of PharmacologyInstitute of Pharmacology

School of MedicineSchool of MedicineShandong UniversityShandong University

louhaiyan@sdu.edu.cnlouhaiyan@sdu.edu.cn

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Components of Basal Ganglia

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1. Components of Basal Ganglia

1. Caudate Nucleus 1. Caudate Nucleus (( 尾状核）尾状核）2. Putamen 2. Putamen (( 壳核）壳核）3.3.Globus Pallidus (GP)Globus Pallidus (GP) （苍白球，旧纹状体）（苍白球，旧纹状体）44. Substantia Nigra. Substantia Nigra （黑质）（黑质）

Pars CompactaPars Compacta (SNc) (SNc) (( 致密部）致密部） Pars Reticulata (SNr)Pars Reticulata (SNr) （网状部）（网状部）

55. Subthalamic Nucleus (STN) . Subthalamic Nucleus (STN) (( 丘脑底核）丘脑底核）

新纹状体纹状体

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2. Medium spiny neuron in striatum (MSN, 中型多棘神经元 )

1) MSN is the main efferent neurons in striatum;

2) MSN 的传入 :

Glu neurons in cortex

DA neurons in SNc

GABA neurons in striatum

Ach neurons in striatum

MSN 树突远端

MSN 胞体和树突近端

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3)MSN dendrite 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）

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

1) direct pathway （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

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2) indirect pathway ( 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

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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 抑制间接通路

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4.Diseases related with dysfunction of Basal ganglia

Parkinson disease Hutington’s disease (Chorea)

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A disease is mainly manifested by

extrapyramidal system motor dysfunction

because of degenerative disorder of CNS.

Parkinson’s Disease

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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 )

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First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.”

“paralysis agitans” ( 震颤麻痹 )

Parkinson’s Disease History

James C. Parkinson

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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

Parkinson’s Disease History

Muhammad Ali in Alanta OlympicMuhammad Ali in Alanta Olympic

Parkinson’s DiseaseParkinson’s Disease

Katharine Hepburn Michael·J·Fox

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Parkinson’s Disease (PD)-Symptoms

1. Resting tremor ( 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

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5. Others Abnormality of posture and gait

Handwriting

Memory impairment, confusion,

disorientation

Cognitive deficits

Depression

Parkinson’s Disease (PD)-Symptoms

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Presymptomatic phase

Onset

SleepOlfactory*MoodAutonomic system

Diagnosis

Early nonmotor symptoms Specific symptoms

Motor

PD symptoms

Dopaminergic neuron loss in PD

% R

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% R

emai

nin

g

Do

pam

ine

rgic

Neu

ron

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op

amin

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ic N

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Time (years)

Nonmotor

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.

*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.

Halperin et al. Neurotherapeutics. 2009;6:128-140.Lang. Neurology. 2007;68:948-952. Ross et al. Ann Neurol. 2008;63:167-173.

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From 1997, April 11th was set as World Parkinson's Disease Day, in memory of the birthday of James Parkinson-- the doctor who described PD.

World Parkinson’s disease day

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Epidemiology of PD

The second most common neurodegenerative

disorder after Alzheimer’s disease (AD). Increase with age (1% population >65 years old) Mean age at onset: 60 years old

85% of patients are over 65 years old

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Classification

1.Primary PD ： unknown

2.Secondary: Parkinsonism

Cerebral arteriosclerosis

Encephalitis( 脑炎 )

Drug poison( 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

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Etiology of PD

Unknown:

Increasing age (rare in those < 50; early or young onset)

More often to occur in families with relatives with PD Alpha-synuclein/Parkin/LRRK2/DJ-1 etc

Environmental factors (pesticides, rural residence)

Head trauma? Infection?

Caffeine and smoking have been found to be protective

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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 head injury

Decreased risk Caffeine intake Smoking cigarettes Anti-oxidants in diet

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Animal model of PD

MPTP 6-OHDA Rotenone Paraquat

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1. Dopamine (DA) theory

Pathophysiology

DA neuronal degeneration in

substantia nigra

reduced or lack of dopamine

in the striatum

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PD Pathology

Normal PD

substantia nigra substantia nigra

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Nigrosriaial Dopamine Pathway

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核

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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

Dopamine theory

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

出现 PD的症状

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Dopamine theory

Ach

黑质

纹状体

DA

DA(—) ( ＋ )

调节运动功能

脊髓前角运动神经元

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Pathogenesis

DA neuronal degeneration in substantia nigra( 黑质 )

1. Dopamine (DA) theory

↓DA synthesis

reduced or lack of dopamine in the striatum↓the function of DA in the nigro-striatal DA pathway

↑the function of Ach

muscular tension

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DA 氧化代谢

H2O2 、 O-

2

ComplexⅠ 抗氧化物（谷胱甘肽）

·OH 、 O+

2

Fe3+

促进神经膜类脂氧化

破坏 DA 神经细胞膜功能

黑质

Pathogenesis

2. Oxidative stress - free radical theory

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Treatment of Parkinson’s disease

No cure for PD Dopaminergic medication Non-dopaminergic medication Other strategies

Surgical interventionRegular exercise

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Antiparkinsonism drugs

DA

Ach

Dopaminomimetic Drugs

Central Anticholinergic Drugs

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AADC

TH: 酪氨酸羟化酶

TH

AADC:L- 芳香族氨基酸脱羧酶

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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

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1. Precursor of DA

　　　—— levodopa （ L-dopa, 左旋多巴）

Levodopa Dopamine

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【 Pharmacological actions and mechanism 】

Penetrate BBB into the brain

Decarboxylated( 脱羧 ) by AADC to DA

Supply DA to striatum

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AADC

TH: 酪氨酸羟化酶

TH

AADC:L- 芳香族氨基酸脱羧酶

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【 Clinical use 】

widely used for all types of PD patients

1. Parkinson’s 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 gradually decreased, little effect

after 3-5 years

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Characteristics:

(1) have good effect on mild and younger patients, less

effect on severe and elderly patients

(2) more effective for musclar rigidity and akinesia ( 运

动不能 ), less effective for resting tremor, difficult to

improve the dementia( 痴呆 )

(3) slow onset, initial effective time is 2-3 w, 1-6 m to

most effective (Emax)

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(4) not effective for Parkinsonium caused by

phenothiazines( 吩噻嗪类 ) 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 )

Characteristics:

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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

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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

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【 Pharmacokinetics 】

1. Absorption

oral, absorbed by small intestine, t1/2 1-3h

Bioavailability is affected by gastric emptying,

gastric acid pH

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【 Pharmacokinetics 】

2. Distribution and metabolism

Levodopa

COMTreuptake MAO

MAO: 单胺氧化酶COMT: 儿茶酚胺 -O- 甲基转移酶

3. Elimination: kidney

—

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【 Adverse reactions 】1. early reactions ：

(1) Gastrointestinal effect: 80%

anorexia( 厌食 ), nausea, vomiting

tolerance after several weeks

domperidone( 多潘立酮，吗丁啉 ) D2-R blocker

(2) Cardiovascular effects:

orthostatic hypotension ( 直立性低血压 ) 30%

arrhythmias — blocker

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【 Adverse reactions 】

2. long-term reactions

(1) Hyperkinesia( 运动过多症 , dyskinesia, 运动障碍 ):

90% ( ＞ 2 years)

　 hand, feet, body — abnormal choreoathetoid movements

( 舞蹈样手足徐动症 )

over stimulation of DA-R involuntary movement ( 不自主运动 )

orofacial (triad) : sucking, licking the tongue, chewing

DA-R blocker

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(2) Fluctuations in response( 症状波动 ):

on-off phenomena

40%-80% (3-5 years)

(3) Psychic disorders

Clozapine ( 氯氮平 ) ： D4

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【 Drug interactions 】

VitB6:

coenzyme of AADC, increase the activity AADC

Antipsychotic drugs:

block DA-R of Nigro-striatal system,

weaken DA function

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Levodopa: The Cornerstone of PD Therapy

Levodopa provides substantial antiparkinsonian symptom control, and significantly improves patient quality of life1

Levodopa is the most efficacious antiparkinsonian medication in moderate and advanced disease

Levodopa provides relatively rapid symptomatic benefits2,3

Levodopa is generally well tolerated with few initial side effects

Levodopa continues to provide antiparkinsonian benefits through the course of the illness

All PD patients eventually require levodopa therapy 1. Louis ED, et al. Arch Neurol. 1997;54:260-264.2. Olanow CW, et al. Neurology. 2001;56:S1-S86.3. Agidy et al. Lancet. 2002;360:575.

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2. Synergetic agents of L-dopa

( 左旋多巴的增效药）

(1)AADC ( 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）

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Metabolism of L-dopa

L-DOPA DAAADC

COMT3-OMD

L-DOPA

Carrier

3-OMD

DAAADC

degradation

MAO-B COMT

reuptake

( 3-O- 甲基多巴 )

BBB BrainPeriphery

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(1) AADC ( 氨基酸脱羧酶 ) inhibitors (≠BBB)

L-DOPA DAAADC

COMT3-OMD

L-DOPA

Carrier

3-OMD

DAAADC

degradation

MAO-B COMT

uptake

( 3-O- 甲基多巴 )

BBB BrainPeriphery

X

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(1) AADC ( 氨基酸脱羧酶 ) inhibitors

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)

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(2) MAO-B inhibitors ( ＝ BBB)

L-DOPA DAAADC

COMT3-OMD

L-DOPA

Carrier

3-OMD

DAAADC

X

degradation

MAO-B COMT

uptake

( 3-O- 甲基多巴 )

BBB BrainPeriphery

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(2) MAO-B inhibitors- Selegiline ( 司来吉兰 )

hypertensive crisis

MAO-B: CNS (nigrostriatal)

selegiline ( 司来吉兰 ):

BBB permeable

reduce the administrated L-dopa dose and “on-off

response”

antioxidant effect

low dose ( ＜ 10mg/d) —only inhibit MAO-B→DA↑

high dose ( ＞ 10mg/d)—inhibit MAO-A too →

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(3) COMT inhibitors (≠or ＝ BBB)

L-DOPA DAAADC

COMT3-OMD

L-DOPA

Carrier

3-OMD

DAAADC

X

degradation

MAO-B COMT

uptake

( 3-O- 甲基多巴 )

BBB BrainPeriphery

X

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Periphery:

CNS: DA degradation↓→ DA in CNS↑

(3) COMT inhibitors (≠or ＝ BBB)

L-DOPA degradation↓

3-OMD (3-O- 甲基多巴 )↓

carrier available for L-DOPA↑

L-DOPA that reach the brain↑

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nitecapone ( 硝替卡朋 ): periphery

Tocapone( 托卡朋 ): periphery and CNS

Entacapone( 安托卡朋 ): periphery

(3) COMT inhibitors (≠or ＝ BBB)

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Dopamine receptors

five main subtypes: D1 ~D5

D1-like receptors: D1, D5 excitation

D2-like receptors: D2,D3, D4 inhibition

3. DA receptor agonists

Nigro-striatal system:

D1-like receptor (D1,D5)

D2-like receptor (D2, D3)

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Bromocriptine ( 溴隐亭 ): D2 agonism ,

D1 partial antagonism

Pramipexole ( 普拉克索 ): D2 agonism

Ropinirole ( 罗平尼咯 ): D2 agonism

Lisuride ( 利修来得 ): D2 agonism,

D1 weak antagonism

3. DA receptor agonists

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Bromocriptine ( 溴隐亭 )

1. Small dose:

stimulate D2-like R in tuberoinfundibular

　　　　　　　　　　　　　（结节漏斗部） reduce 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 )

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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, last short (6-8w), synergistic

action with L-dopa

Dopamine receptors

DADA

L-DOPAL-DOPA

3-OMD3-OMD

DADA

DopamineDopamineagonistsagonists

COMT COMT inhibitorsinhibitors

CarbidopaCarbidopa

MAO-BMAO-B inhibitorsinhibitors DOPACDOPAC

DA DA

3-MT3-MT

DADA

DA DA

AADCAADC

DADACOMTCOMT

inhibitor*inhibitor*

L-DOPAL-DOPA

DADADADA

Blood-brain barrierPeriphery BrainNeuron

Sites of Action of PD Drugs

*Only tolcapone inhibits COMT in brain.

L-DOPA = levodopa3-OMD = 3-O-methyldopaDA = dopamine

AADC = aromatic acid decarboxylase DOPAC = dihydroxyphenylacetic acid3-MT = 3-methoxytyramine

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Ⅱ Central Anticholinergic Drugs

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Trihexyphenidyl ( 苯海索 , artane, 安坦 )

Blocking the M-R ,↓cholinergic function in

the nigrostriatal.

Effective for Parkinsonism caused by

phenothiazines( 吩噻嗪类）

Improve the tremor of PD, little effect on

bradykinesia( 动作迟缓 ) and rigidity

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Surgery -

Deep Brain StimulationBrain pacemaker, sends electrical impulses

to brain to stimulate the subthalamic nucleus.

Improves motor functions and reduce motor complications.

Complications include: brain hemorrhage, seizures, death.

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Summary

1. L-dopa is used with which drug and why?

2. Describe the classification of anti-PD drugs and their mechanism of action

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