Dopamine and Parkinsons

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Dopamine and Parkinsons
Matthew Rice matt.rice_at_utoronto.ca Rachel
Whitty rachel.whitty_at_utoronto.ca Sabina
Wong sabina.wong_at_utoronto.ca
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What is Parkinsons?
Lynda diagnosed with Parkinsons at 34
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What is Parkinsons?

• Parkinsons is a neurodegenerative disease.
• Movement is normally controlled by dopamine, a
  chemical that carries signals between the nerves
  in the brain.
• When cells that normally produce dopamine die,
  the symptoms of Parkinsons appear.

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Main Symptoms - MIST
M muscle rigidity I impaired balance S
slowness and stiffness T - tremor
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Other Motor Symptoms

• Soft speech
• Problems with handwriting (small)
• Reduced facial expression
• Shuffling when walking
• Muscle pain
• Stooped posture

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Other Non-motor Symptoms

• Constipation
• Sleep disturbances
• Fatigue
• Bladder urgency and frequency
• Dizziness on standing
• Depression feeling sad, having less energy or
  losing interest in activities
• Memory problems

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Progression of Parkinsons

• Currently, there is no cure
• Progresses at different rates for each person
• Medication will need to be adjusted as symptoms
  change
• Other non-motor symptoms may appear such as
  depression, difficulty swallowing, sexual
  problems, or cognitive changes
• May progress more quickly in people who are older
  when symptoms begin
• May progress more slowly when the main symptom is
  tremor
• Parkinsons is not a mental disease, although 30
  of people with Parkinsons will eventually
  develop dementia

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Incidence and Risk Factors

• Affects 100 000 Canadians both men and women,
  from all ethnic backgrounds
• Not only found in older people it can affect
  people as young as 30 or 40, although average age
  of onset is 60
• Genetic predisposition
• Environmental factors (toxins)

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Pathophysiology

• Results from the loss of dopaminergic neurons of
  the basal ganglia
• Specifically affects the pathway going from the
  substantia nigra to the striatum
• As with most brain tissue, the neurons atrophy
  with age
• If this loss of neurons becomes too great to
  reduce dopamine levels by about 90 then
  Parkinsons symptoms result

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Pathophysiology

• Movement disorders arise from this disfunctioning
  of the nigrostriatal pathway
• Normally input from the substantia nigra to the
  striatum can promote movement, both by the
  excitation of a direct pathway and inhibition of
  an indirect pathway
• In Parkinsons patients loss of dopaminergic
  neurons in this pathway, resulting in increased
  difficulty initiating movements
• The movement pathway involved is related to those
  movements guided by internal cues and movements
  guided by external cues are unaffected

AKA STRIATUM
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Drug-induced Parkinsonism

• The use of dopamine 2 receptor antagonists in the
  treatment of psychotic disorders, such as
  schizophrenia, can result in some serious side
  effects
• When these drugs block D2 receptors in the
  nigrostriatal pathway, disorders of movement
  resembling Parkinsons disease can result
• These side effects are known as extrapyramidal
  symptoms (EPS)

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Chemical Model of Parkinsons

• There are many hypotheses for the cause of
  Parkinsons disease, the most notable being
  environmental factors such as exposure to toxins
• A model has been developed for use in monkeys
  using the chemical MPTP (1-methyl 4-phenyl
  1,2,3,6-tetrahydropyridine)
• MPTP, a contaminant in synthetically made heroin,
  was first discovered in drug addicts that showed
  Parkinsons symptoms
• MPTP is metabolized by monoamine oxidase, which
  is highly concentrated in dopaminergic neurons,
  to MPP
• MPP concentrates in substantia nigra neurons by
  binding to neuromelanin and causes cell toxicity
  by disrupting the electron transport chain in
  mitochondria
• As a result, exposure to MPTP leads to
  Parkinsons disease and can be used in animal
  models to study the disease

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Mechanisms for Neuronal Degeneration

• Many hypotheses as to the biochemical mechanisms
  that lead to neuronal cell death occurring in
  Parkinsons disease
• Role of mitochondrial dysfunction and oxidative
  stress in contributing to neuronal cell death in
  the substantia nigra
• Inhibitors of Complex I of the mitochondrial
  electron transport chain have been shown to
  reproduce the pathological features of the
  disease
• Mis-folding and abnormal degradation of proteins
  within the cell has also been associated with
  increased dopaminergic neuronal death
• Increased levels of the enzyme monoamine oxidase
  (MAO) results in increased generation of H2O2
  which cause oxidative damage to mitochondria in
  the neuron
• Increased levels of ferrous iron, which
  facilitates the conversion of H2O2 to reactive
  and damaging hydroxyl radicals, were observed in
  dopaminergic neurons of Parkinsons patients
• Lower levels of protective mechanisms againts
  oxidative agents such as glutathione peroxidase
  were observed in the substantia nigra of patients
  with Parkinsons disease

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Treatment Options
Drug therapy is only for symptom management,
there is no drug that can cure or slow the
progression of the disease.

• Non-pharmacologic education, exercise,
  nutrition, support
• Physical therapy helps mobility, flexibility and
  balance
• Occupational therapy helps with daily activities
• Speech therapy helps with voice control
• Exercise helps muscles and joints and improves
  overall health and well-being

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Treatment Options

• MAO type B inhibitors prevents dopamine
  metabolism within the brain
• Usually first drug of choice if disease in early
  stages
• May be neuroprotective
• Dopamine agonists directly stimulate dopamine
  receptors.
• Also an initial drug of choice if the patient is
  functionally young
• Dopamine replacement therapy Levodopa immediate
  precursor to dopamine, converted to dopamine in
  brain
• When more symptom relief is required
• Effect wears off over time
• Patients can develop motor fluctuations (levodopa
  induced dyskinesias)

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Treatment Options

• COMT (catechol-O-methyltransferase) inhibitors
  used in conjunction with levodopa
• Reduces motor fluctuations caused by levodopa
• Amantadine Used with levodopa, for
  antidyskinesia effect, MOA unknown
• Anticholinergics blocks acetylcholine effects
  (i.e. tremor) that are increased in the absence
  of dopamine
• Surgery deep brain stimulation of the
  subthalamic nucleus for severe disabling
  dyskinesias.

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Summary

• Parkinsons is a neurodegenerative disease that
  impairs motor movement due to the loss of
  dopaminergic neurons in the substantia nigra. It
  occurs mainly in people over the age of 60.
• This neurodegeneration may be a result of a
  genetic predisposition, or by environmental
  factors such as toxins and drugs that increase
  the oxidative stress of dopaminergic neurons
• Symptoms result when dopamine levels are reduced
  by about 90
• The main symptoms are MIST Muscle rigidity,
  Impaired balance, Slowness and Stiffness and
  Tremor
• There is no cure. Treatment for Parkinsons
  disease targets the alleviation of symptoms only
• Non-pharmacological therapy includes physical,
  occupational and speech therapy
• Pharmacological therapy includes dopamine
  agonists, MOA-B inhibitors, dopamine replacement
  therapy, COMT inhibitors, amantadine,
  anticholinergics and surgery.

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References

• Cognitive Neuroscience 2nd Edition. W.W. Norton
  Company. New York. 2002.
• Biological Psychology 4th Edition. Sinauer
  Associates Inc. Massachusetts. 2005
• Essential Psychopharmacology 2nd Edition.
  Cambridge University Press. Cambridge. 2000.
• Human Molecular Genetics 16 (2), R183 R194,
  (2007).
• Neurology 56, 375-82, (2001).
• Clinical Neuroscience Research 6, 261281 (2006).

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References

• Monoamine Oxidase and its affects on the brain
  http//pspinformation.com/nutrition/enzymes/mao.sh
  tml
• Parkinson Society Canada
• http//www.parkinson.ca
• Lew, M. 2007. Overview of Parkinson's Disease.
  Pharmacotherapy 27(12)155S-160S.
• Chen JJ, Swope DM. 2007. Pharmacotherapy for
  Parkinson's Disease. Pharmacotherapy.
  27(12)161S-173S.