Motor systems II: The basal ganglia and Drugs used for the

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Transcript Motor systems II: The basal ganglia and Drugs used for the

Motor systems II: The basal ganglia and Drugs
used for the treatment of Parkinson’s disease
Lou haiyan(娄海燕)
Institute of Pharmacology
School of Medicine
Shandong University
[email protected]
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Components of Basal Ganglia
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1. Components of Basal Ganglia
1. Caudate Nucleus (尾状核)
新纹状体
2. Putamen (壳核)
3.Globus Pallidus (GP) (苍白球,旧纹状体)
4. Substantia Nigra (黑质)
Pars Compacta (SNc) (致密部)
Pars Reticulata (SNr) (网状部)
5. Subthalamic Nucleus (STN) (丘脑底核)
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
MSN树突远端
GABA neurons in striatum
Ach neurons in striatum
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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Parkinson’s Disease
A disease is mainly manifested by
extrapyramidal system motor dysfunction
because of degenerative disorder of CNS.
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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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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
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Parkinson’s Disease History
 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
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Parkinson’s Disease
Muhammad Ali in Alanta Olympic
Michael·J·Fox Katharine Hepburn
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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Parkinson’s Disease (PD)-Symptoms
 5. Others
 Abnormality of posture and gait
 Handwriting
 Memory impairment, confusion,
disorientation
 Cognitive deficits
 Depression
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PD symptoms
% Remaining
Dopaminergic Neurons
Onset
Diagnosis
Dopaminergic neuron loss in PD
Nonmotor
Motor
Sleep
Olfactory*
Mood
Autonomic system
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.
World Parkinson’s disease day
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.
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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)
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Risk of Parkinson’s Disease
Increased risk






Age
High Body Mass Index
Male gender
Family history
Depression
Environment factors




Decreased risk
 Caffeine intake
 Smoking cigarettes
 Anti-oxidants in diet
rural living
well-water drinking
welding
head injury
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Animal model of PD




MPTP
6-OHDA
Rotenone
Paraquat
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Pathophysiology
1. Dopamine (DA) theory
DA neuronal degeneration in
substantia nigra
 reduced or lack of dopamine
in the striatum
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PD Pathology
Normal
substantia nigra
PD
substantia nigra
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Nigrosriaial
Dopamine
Pathway
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核
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Dopamine theory
黑质内DA能神经
当DA合成减少或
DA神经元退化时
元发生退行性变
胆碱能神经元
多巴胺能神经元
白质
传入
背侧 灰质
后角
前角
传出
腹侧
ACh兴奋前角
运动神经元
出现PD
的症状
DA抑制前角
运动神经元
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黑质
Dopamine theory
DA
纹状体
DA
(—)
Ach
(+ )
脊髓前角运动神经元
调节运动功能
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Pathogenesis
1. Dopamine (DA) theory
DA neuronal degeneration in substantia nigra(黑质)
 ↓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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Pathogenesis
2. Oxidative stress - free radical theory
Fe3+
DA氧化代谢
H2O2、O-2
ComplexⅠ
抗氧化物(谷胱甘肽)
黑质
·OH 、O+2
促进神经膜类脂氧化
破坏DA神经细胞膜功能
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Treatment of Parkinson’s disease
No cure for PD
 Dopaminergic medication
 Non-dopaminergic medication
 Other strategies
 Surgical intervention
 Regular exercise
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Antiparkinsonism drugs
Dopaminomimetic Drugs
Central Anticholinergic Drugs
DA
Ach
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TH:酪氨酸羟化酶
AADC:L-芳香族氨基酸脱羧酶
TH
AADC
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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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TH:酪氨酸羟化酶
AADC:L-芳香族氨基酸脱羧酶
TH
AADC
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【Clinical use】
1. Parkinson’s disease: symptomatic treatment
widely used for 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
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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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Characteristics:
(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)
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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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肠
食物中芳香族氨基酸 菌
肝中MAO
苯乙醇胺
脱羧酶
肝功能
清除
羟化酶
酪胺和苯乙胺
脑组织
血浓度
羟苯乙胺
拟去甲肾上腺
素等递质
脑内
左旋多巴 转变
神经传导障碍
肝昏迷
去甲肾上腺素
改善神经传导
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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
MAO:单胺氧化酶
COMT:儿茶酚胺-O-甲基转移酶
reuptake
MAO
COMT
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)
over stimulation of DA-R
 involuntary movement (不自主运动)
orofacial (triad) : sucking, licking the tongue, chewing
hand, feet, body — abnormal choreoathetoid movements
(舞蹈样手足徐动症)
 DA-R blocker
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(2) Fluctuations in response(症状波动):
 40%-80% (3-5 years)
 on-off phenomena
(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
AADC
DA
reuptake
L-DOPA
L-DOPA
AADC
DA
MAO-B
COMT
3-OMD
( 3-O-甲基多巴)
3-OMD
COMT
degradation
Carrier
Periphery
BBB
Brain
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X
(1) AADC (氨基酸脱羧酶) inhibitors (≠BBB)
AADC
DA
uptake
L-DOPA
L-DOPA
AADC
DA
MAO-B
COMT
3-OMD
( 3-O-甲基多巴)
3-OMD
COMT
degradation
Carrier
Periphery
BBB
Brain
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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)
AADC
DA
uptake
L-DOPA
AADC
DA
X
L-DOPA
MAO-B
COMT
3-OMD
( 3-O-甲基多巴)
3-OMD
COMT
degradation
Carrier
Periphery
BBB
Brain
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(2) MAO-B inhibitors- Selegiline (司来吉兰)
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 →
hypertensive
crisis
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(3) COMT inhibitors (≠or= BBB)
DA
uptake
L-DOPA
L-DOPA
AADC
DA
X
MAO-B
COMT
3-OMD
( 3-O-甲基多巴)
3-OMD
X
AADC
COMT
degradation
Carrier
Periphery
BBB
Brain
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(3) COMT inhibitors (≠or= BBB)
 Periphery:
L-DOPA degradation↓
3-OMD (3-O-甲基多巴)↓
carrier available for L-DOPA↑
L-DOPA that reach the brain↑
 CNS: DA degradation↓→ DA in CNS↑
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(3) COMT inhibitors (≠or= BBB)
nitecapone (硝替卡朋): periphery
Tocapone(托卡朋): periphery and CNS
Entacapone(安托卡朋): periphery
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3. DA receptor agonists
Dopamine receptors
 five main subtypes: D1 ~D5
D1-like receptors: D1, D5
excitation
D2-like receptors: D2,D3, D4
inhibition
Nigro-striatal system:
D1-like receptor (D1,D5)
D2-like receptor (D2, D3)
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3. DA receptor agonists
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
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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
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Sites of Action of PD Drugs
Periphery
Blood-brain barrier
Brain
Neuron
COMT 3-OMD
inhibitors
L-DOPA
L-DOPA
MAO-B
inhibitors DOPAC
AADC
Carbidopa
DA
DA
DA
DA
DA
DA
*Only tolcapone inhibits
COMT in brain.
L-DOPA = levodopa
3-OMD = 3-O-methyldopa
DA = dopamine
Dopamine receptors
AADC = aromatic acid decarboxylase
DOPAC = dihydroxyphenylacetic acid
3-MT = 3-methoxytyramine
DA
COMT 3-MT
inhibitor*
Dopamine
agonists
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 Stimulation
 Brain 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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