La Vita Bloccata. V. Rispoli Antiparkinsonian Therapy. V. Rispoli. Visit

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1 Università degli Studi Magna Græcia di Catanzaro La Vita Bloccata Antiparkinsonian Therapy V. Rispoli Visit CNS Disorders CNS Disorders 2 Parkinson s disease Objectives To know the biochimical and neural basis for the disorder To undestand the clinical pharmacology of levodopa To undestand the problems around levodopa therapy in parkinson disease To undestand the neural circuitry involved in the disease 3 1

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3 Micheal J. Fox Parkinson Disease yer_detailpage&v=jodvgh4egfi#t=0s 7 Parkinson s / Etiopathogenesis Cerebral atherosclerosis Viral encephalitis (e.g. von Economos encephalitis) Side effects of several antipsychotic drugs (i.e., phenothiazides, butyrophenones, reserpine) Environmental factors and neurotoxins (e.g. MPTP) V. Rispoli Oliver Sacks Risvegli 9 3

4 Oliver Sacks Risvegli 10 Risveglio alla vita

5 Epidemiologia / incidenza In termini generali, l'incidenza misura la proporzione di "nuovi eventi" (nuovi casi di malattia) che si verificano in una popolazione in un dato lasso di tempo Per questo motivo, possiamo dire che l'incidenza rappresenta la proporzione di individui che vengono colpiti dalla malattia in un determinato periodo di tempo L'incidenza, quindi, misura il numero di nuovi casi nel periodo di tempo ed individua il rischio (cioè la probabilità) di contrarre la malattia cui è soggetto un animale esposto in quella popolazione 13 Epidemiologia / prevalenza La prevalenza misura la proporzione di individui di una popolazione che, in un dato momento, presentano la malattia 14 La Malattia di Parkinson 15 5

6 M. Di Parkinson / epidemiologia Disturbo neurologico che affligge 4 milioni di persone nel mondo Solo 1,5 milioni di pazienti negli USA In Italia la prevalenza è di casi 3% della popolazione con età > 60 anni 10% di prevalenza nella popolazione > di 80 anni 10% circa con esordio prima dei 40 anni (Young-onset of PD) 16 M. di Parkinson & demenza: epidemiologia

7 Parkinson s disease 19 Parkinson s Disease What is Parkinson's disease? In 1817, James Parkinson described six patients with involuntary tremulous motion lessened muscular power, and a propensity to bend the trunk forwards

8 Parkinson s / Etiopathogenesis Appears Later in Life Continuous Progressive Neurological Disease o thereby causing increasing disability of movement no cure Parkinson s disease Primary Symptoms Appear slowly and in no particular order Tremor Rigidity Bradykinesia Gait disorder Loss of Balance 24 8

9 Parkinson s: Symptoms Tremor 25 Parkinson s: Symptoms Rigidity 26 Parkinson s: Symptoms Bradykinesia 27 9

10 28 Parkinson s disease: Gait disorders 29 Parkinson s disease: Symptoms 30 10

11 Parkinson s disease: Gait disorders JAMA 2003; 289(3): Parkinson s disease Usually Other Accompanied Autonomic Deficits Seen Later in Disease Process: Orthostatic Hypotension Dementia Dystonia Ophthalmoplegia Affective Disorders

12 The nigro-striatal dopaminergic pathway dopamine-producing neurons die in PD 34 Parkinson s: dopaminergic pathways Nigrostriatal: Mesolimbic: Mesocortical: Substantia nigra (A9) to Striatum (Basal Ganglia Regulation of movementl Sensitive to MPTP, methamphetamine Ventral tegmental Area (A10) to Nucleus Accumbes Regulation of mental well-being Less sensitive to MPTP, methamphetamine Ventral Tegmental Area (10) to Nucleus Accumbens Regulation of Mental well-being Loss sensitive to MPTP, methamphetamine 35 What Regulates Movement? 36 12

13 The Basal Ganglia The Basal Ganglia Consists of Five Large Subcortical Nuclei That Participate in Control of Movement Caudate Nucleus Putamen Globus Pallidus Subthalamic Nucleus Substantia Nigra 37 The Basal Ganglia Role of basal ganglia 1. Inhibit muscle tone throughout the body 2. Select & maintain purposeful motor activity while suppressing useless/unwanted patterns of movement 3. Coordination of slow, sustained movements (especially those related to posture & support) 4. Help regulate activity of the cerebral cortex 38 Parkinson s: extrapiramidal system 39 13

14 Parkinson s: neural circuitry 40 Dopamine Major NT regulating subconscious movements of skeletal muscles majority located in the terminals of pathway stretching from the neuronal cell bodies in SNc to the striatum generally inhibits the function of striatal neurons & striatal outputs when dopamine production is, a chemical imbalance occurs affecting movement, balance and gait 41 Parkinson s disease: pathophysiology 42 14

15 Parkinson s: neuropathology The substantia nigra 43 Parkinson s: neuropathology 44 Parkinson s: neuropathology 45 15

16 Parkinson s / neurochemistry The Dopaminergic Neurons in the Basal Ganglia are mainly affected Acetylcholine within striatum is a tonically activated neuron It impinges on GABA Neuron by an Excitatory Action GABA Neuron has an Inhibitory Action on the Substantia Nigra from Substantia Nigra, has a Dopaminergic Feed Back Loop Back to Striatum which gets Loss Giving Signs and Symptoms of Parkinson Disease 46 Parkinson s / neurochemistry The balance of the five large Subcortical Nuclei are responsible for smooth motor movements The primary input is from the Cerebral Cortex, and the output Is directed through the thalamus back to the Prefrontal, Premotor, and Motor Cortex The motor function of the Basal Ganglia are therefore mediated by the Frontal Cortex Neurotransmitters in Basal Ganglia Include Serotonin, Acetylcholine, GABA, Enkephalin, Substance P, Glutamate, and Dopamine Dopamine from Substantia Nigra decreases release of acetylcholine from striatum. 47 Parkinson s: neural circuitry 48 16

17 Parkinson s: neural circuitry 49 Parkinson s: neural circuitry 50 Parkinson s disease: neurochemistry 51 17

18 Parkinson s disease: neurochemistry 52 Effects of PD on Neural Function - Stn - GP GABA Enk + Cerebral Cortex Glutamate + D 2 DA - D 1 EP(Gpi)/SNr GABA SP - + Normal function Thalamus - Stn GP GABA Enk Cerebral Cortex Glutamate + D 2 DA D 1 EP(Gpi)/SNr GABA SP Thalamus Dopamine deficiency (PD) 53 The nigro-striatal dopaminergic pathway CORTECCIA GLU T A L + GABA + _ Ach _ + STRIATO A M O PALLIDO _ R DA C SCHEMA ESEMPLIFICATO DEL CIRCUITO EXTRAPIRAMIDALE SUBSTANTIA NIGRA 54 18

19 Parkinson s disease: neurochemistry

20 Parkinson s / Etiopathogenesis Mechanisms of Neurodegeneration Dauer et al Neuron Vol. 39: Parkinson s / Etiopathogenesis Genetic mechanism No convincing epidemiological evidence, although rare familial Parkinson s exists (α-synuclein and parkin mutants) Environmental toxicants Although some compounds cause parkinsonism (e.g. MPTP or Mn), and there are epidemiological association, there is no compelling link to a specific toxicant. Microbiological (viral or less) Infections can caused parkinsonism (e.g. von Economos encephalitis), but no such link exists in most cases.. Biochemical defect Changes in mitochondrial function (possibly mitochondrial genetics) may be a factor (speculative at present). Premature apoptotic event? 59 Parkinson s: Etiopathogenesis 60 20

21 Parkinson s / Etiopathogenesis Pesticides, herbicides, industrial chemicals - contain substances that inhibit complex I in the mitochondria 61 Parkinson s: Etiopathogenesis 62 Parkinson s: Etiopathogenesis 63 21

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23 Parkinson s disease: experimental model 67 Parkinson s disease: experimental model

24 Parkinson & Parkinsonism 1. Most cases are unexplained 2. The frozen addict. An impurity in synthetic heroin. taken up by the dopamine transporter (expressed only in dopaminergic cells). Kills cells. 3. The influenza pandemic (worldwide epidemic) of 1918, which killed 20 million people. The flu specifically killed dopaminergic neurons in many people ( Awakenings ). 4. Synuclein: a protein of unknown function. Dominant mutations, leading to intracellular deposits. 5. Smoking protects against PD. 70 Kitchen Chemistry & PD O C 2 H 5 OC N-CH 3 Meperidine C 3 H 7 O N-CH 3 4-propyloxy-4- phenyl-nmethylpiperidine (meperidine analog) Accidentally Synthesized... N CH 3 MPTP MPP + N CH 3 71 MPTP-induced human parkinsonism 72 24

25 73 MPTP-induced human parkinsonism 74 Drug-induced human parkinsonism 75 25

26 Drug-induced human parkinsonism 76 Drug-induced human parkinsonism

27 Drug-induced human parkinsonism 79 Drug-induced human parkinsonism 80 Drug-induced human parkinsonism 81 27

28 Drug-induced human parkinsonism 82 Parkinson & neurodegeneration Environmental factors and neurotoxins Pesticides, herbicides, industrial chemicals - contain substances that inhibit complex I in the mitochondria 83 Parkinson & neurodegeneration 84 28

29 Parkinson & neurodegeneration 85 Parkinson & neurodegeneration 86 Parkinson s disease: neurochemistry Dopamine & neurodegeneration HO H 2 C CH2 NH 3 + reactive: oxidative damage? HO dopamine 87 29

30 Parkinson & neurodegeneration 88 Parkinson & neurodegeneration 89 Parkinson & neurodegeneration Proposed Role of Apoptosis in MPTP Toxicity Vila and Przedborski, Nat. Rev. Neurosci. 4:365,

31 Parkinson & neurodegeneration ROS Apoptosis OXIDATIVE STRESS AND NEURODEGENERATION Lipids Proteins DNA ROS Lipids Proteins 91 Parkinson & neurodegeneration H 2 O 2. Proteins OH. O - Lipids 2 ONOO DNA 92 31