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Models for PARKINSON’S DISEASE By. Jyotirmoy Das Choudhury M.Pharm 1st semester Phamacology Under the Guidance of Mr. Avik Das(M.S.), Lecturer, Pharmacology Department.
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Content Definition. Epidemiology. Clinical features. Biochemical abnormalities. Dopamine synthesis. Pathophysiology. Risk factor. Treatment of PD. New treatment approach. Models. In Vitro Models. In Vivo Models. Summery. References. 2
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DEFINITION Parkinson’s disease is a degenerative disorder of CNS comprising four cardinal feature: bradykinesia, muscular rigidity, resting tremor and postural instability. 3
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EPIDEMIOLOGY The approx annual incidence of PD is age dependent. Ranges from 10 per 100,000 person in sixth decade of life to 120 per 100,000 person in ninth decade of life. The most common movement disorder after Alziemer’s diseases. A higher incidence is reported among males than females with a male to female ratio of up to 2:1. 4
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CLINICAL FEATURES Four cardinal symptoms: ® resting tremor ® bradykinesia muscle rigidity postural insatability 5
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Main Biochemical Abnormality Marked striatal DA depletion “Striatal dopamine deficiency syndrome” At death, DA loss > 90% <50% DA loss is asymptomatic ~70% DA loss for symptom manifestations Severity of DA loss best correlates with bradykinesia in PD 6
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Dopamine synthesis 7
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PATHOPHYSIOLOGY 8
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RISK FACTOR Definite: Old age Highly likely: MZ co-twin with early-onset PD Probable: Positive family history Possible: Herbicides, pesticides, heavy metals, proximity to industry, rural residence, well water, repeated head trauma, etc. Possible protective effect: Smoking 9
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TRETMENT OF PD Treatment of PD mainly may be of two types: Pharmacologic treatment. Non pharmacologic treatment. Surgical treatment of PD. 10
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Pharmacologic Treatment of Parkinson’s Disease It is done by using different classes of drug. The different drugs used in the treament of PD are: 1. Drug affecting brain dopaminergic system a. Dopamine precursor: Levodopa b. Peripheral decrboxylase inhibitor: Carbidopa c. Dopaminergic agonist: Bromocriptine, Ropinirole d. MAO-B inhibitor: Selegiline e. COMT inhibitor: Tolcapone, Entacapone f. Dopamine facilitator: Amantadine 2. Drug affecting brain cholinergic system a. Central anticholinergics: Benzhexol, Procyclidine b. Antihistaminics: Promethazine, Orphenadrine 11
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Sites of Action of Anti-PD Drugs 12
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Nonpharmacologic Treatments Patient/caregiver education Physical therapy Exercise Occupational therapy Speech/language therapy Diet and nutrition Psychosocial interventions 13
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The Surgical Treatment of Parkinson’s Disease Treating PD by surgery was a common practice before the discovery of Levodopa. Surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient. It is done by deep brain stimulation or by implanting Brain pace maker. 14
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New Treatment Approach One of the most promising new drug therapies for the treatment of Parkinson's disease is a new dopamine agonist (a drug that mimics the action of dopamine in the brain). Unlike other dopamine agonists, this new drug is delivered via a delivery system that enables blood levels of the drug to stay consistent throughout the day. Studies have suggested that this new Parkinson's therapy may have properties that not only lessen parkinsonian symptoms, but may also protect nerve cells in the substania nigra from degeneration and death. Clinical trials have been completed for this new Parkinson's therapy and it is currently awaiting FDA approval in the United States for the treatment of the symptoms of early Parkinson's disease. 15
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Models for Parkinson’s Disease Models are required for screening the Anti PD Drug. Models are the replica of the disease state in human i.e. models are the replica of the diseased human. It can be the replica of the signs & symptoms of the disease. Models can use to observe the biochemical changes causing the disease or caused by the disease. 16
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In Vitro Models The In Vitro Models include the following: Culture of Substantia Nigra. Inhibition of Apoptosis in Neuroblastoma SH-SY5Y cells. 17
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In Vivo Models The In Vivo models includes the following: Tremorine & Oxotremorine antagonism. MPTP models for PD. Reserpine antagonism. Elevated body swing test. 18
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Tremorine & Oxotremorine antagonism. Purpose & Rationale: The muscarinic agonists tremorine and oxotremorine induce parkinsonism-like signs such as tremor, ataxia, spasticity, salivation, lacrimation and hypothermia. These signs are antagonized by anticholinergic drugs. 19
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Procedure: 20
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Scoring for TREMOR & Salivation & Lacrimation 21
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Evaluation: Hypothermia: The differences of body temperature after 1, 2 and 3 hr versus basal values are summarized for each animal in the control group and the test groups. The average values are compared statistically. Tremor: The scores for all animals in each group at the three observation periods are summarized. The numbers in the treated groups are expressed as percentage of the number of the control group. 22
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Salivation and Lacrimation The scores for both symptoms for all animals in each group are summarized at the two observation periods. The numbers in the treated groups are expressed as a percentage of the number of the control group. 23
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Modifications: Coward et al. (1977) recommended N-carbamoyl- 2-(2,6-dichlorophenyl)acetamidine hydrochloride (LON-954), a tremorigenic agent, as an alternative to oxotremorine for the detection of anti-Parkinson drugs. Betarbet et al. 2000; indicate that the exposure to the pesticide rotenone causes highly selective dopaminergic degeneration and α-synuclein aggregation in rats. 24
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MPTP models for PD. PURPOSE AND RATIONALE MPTP (N-methyl-4-phenyl-1,2,3,6tetrahydropyridine) has been shown to cause symptoms of Parkinson’s disease in exposed individuals. 25
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Procedure 26
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Evaluation: The severity of parkinsonian symptoms is rated by trained observers using a scale of 0 (normal) to 17 (maximum severity) that assesses: Movement (0: normal;1: reduced; 2: sleepy), Checking movements (0: present; 1: reduced; 2: absent), Attention and blinking (0: normal; 1: abnormal), Posture (0: normal; 1: abnormal trunk; 2: abnormal trunk and tail; 3: abnormal trunk, tail, and limbs; 4: flexed posture), Balance and coordination (0: normal; 1: impaired; 2: unstable; 4: falls), Reactions (0: normal; 1: reduced; 2: slow; 3: absent) Vocalizations (0: normal; 1: reduced; 2: absent). 27
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Modifications: Close and Elliott (1991) studied the behavioral effects of anti-Parkinsonian drugs in normal and MPTP treated marmosets. Lange (1989, 1990) described circling behavior in old rats after unilateral intranigral injection of MPTP. 28
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Reserpine Antagonism PURPOSE AND RATIONALE: Reserpine induces depletion of central catecholamine stores. The sedative effect can be observed in mice shortly after injection, followed by signs of eyelid ptosis, hypokinesia, rigidity, catatonia, and immobility. These phenomena can be antagonized by dopamine agonists. 29
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Procedure: 30
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Evaluation: Locomotor activity and grooming scores of drug treated animals are compared with controls treated with reserpine and vehicle only by analysis of variance. 31
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Summery 1-2 % of the general population over the age of 65 y are the sufferer. Lewy bodies and Lewy neurites particularly in the substantia nigra pars compacta dopaminergic neurons projecting to striatum DA levels is severely reduced in striatum. Resting tremor, bradykinesia, muscle rigidity are the signs. Levodopa and other dopaminergic drugs are used. No treatment which would prevent the continuous degeneration of nerve cells in the substantia nigra and resulting striatal DA loss. No disease-specific biological marker. In Vitro & In Vivo models are used for screening of Anti PD drugs. 32
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References Alfred Goodman Gilman, 2001; Tenth Edition, “The Pharmacological Basis Of Therapeutics.” Page : 552-554. H. Gerhard Vogel (Ed.), 2008; Second Edition, “Drug Discovery and Evaluation: Pharmacological Assays”. Page : 820-822, 824-829. K. D. Tripathi,2009; Sixth Edition, “Essentials of Medical Pharmacology.” Page : 416. 33
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34 Mail id: jdc_pharma@yahoo.in / jdc_13@rediffmail.com