Parkinson's Disease

Question 1

What are the main components of movement control?

Answer 1

Hierarchical: Cortex -> Brainstem -> Spinal cord

The basal ganglia and the cerebellum also modulate movement through the thalamus

Question 2

What are the components of the basal ganglia?

Answer 2

• Caduate nucleus + putamen make the striatum

- Globus pallidus and substantia nigra (implicated in Parkinson’s)

Question 3

What is the role of the basal ganglia?

Answer 3

• Recieves input from the cortex which it relays through the putamen and globus pallidus
• Output on the cortex and spinal cord

Question 4

What is the direct pathway?

Answer 4

• Recieves dopaminergic input from the substantia nigra which binds to D1 receptors and facilitates movement

Question 5

What is the indirect pathway?

Answer 5

• Dopaminergic input on D2 receptors

- Inhibits movement (specifically competing motor patterns)

Question 6

What are the symptoms of Parkinson’s Disease?

Answer 6

• Resting tremor
• Akinesia (impaired movement initiation)
• Bradykinesia (slowing)
• Rigidity due to increased muscle tone
• Postural instability
• Mask-like facial expressions

Question 7

What is the pathology of Parkinson’s?

Answer 7

• Deficiency of dopamine in the striatum
• Dopaminergic neurons of the substantia nigra degenerate (symptoms only appear after 60-80% loss)
• Increased inhibition of movement through D2 indirect pathway

Question 8

What are the known causes of Parkinsons?

Answer 8

• Rare hereditary forms
• Environmental factors
• Trauma

Question 9

What drug is used to model Parkinsons? Why?

Answer 9

• MPTP given to heroin addicts, however contaminated with MPPP which is converted to MPP+ by monoamine oxidase
• Taken up by dopaminergic neurons in the motor regions causing severe Parkinsons

Question 10

How is dopamine synthesised at the synapse?

Answer 10

• From L-tyrosine which is converted to L-Dopa by tyrosine hydroxylase in a rate limiting step
• L-Dopa decarboxylated to dopamine only after crossing BBB

Question 11

How is L-Dopa believed to function as a drug?

Answer 11

• Absorbed by the small intestine with a 2 hour half life (relatively short)
• Broken down by decarboxylation in the brain to create more dopamine

Question 12

How effective is L-Dopa as a treatment?

Answer 12

Relatively good

• 80% of patients show improvement
• 20% restored to normal function

Question 13

Why is L-Dopa typically only used much later in Parkinson’s treatment?

Answer 13

Effectiveness declines quickly due to disease progression and down-regulation of receptors

Question 14

What are the possible side effects of L-DOPA treatment?

Answer 14

• Dyskinesia (involuntary movements) typically after 2 years of therapy relating to L-Dopa peaks
• On/Off effect due to rapid fluctuations of L-Dopa relating to its short half-life
• Nau

Question 15

What are the possible accute side-effects of L-Dopa treatment?

Answer 15

Usually occur in the first weeks of treatment before dissapearing

• Nausea (can be treated with peripheral DA antagonist0
• Hypertension (can be an issue with patients already on anti-hypertensives)
• Schizophrenia-like dellusions and hallucinations
• Confusion, insomnia and nightmares

Question 16

What are L-DOPA combination therapies?

Answer 16

Most L-Dopa broken down at the periphery by DOPA-decarboxylase

• Can be inhibited by co-administering carbidopa (doesn’t cross the BBB)
• Can administer 10 fold less L-DOPA and prevents side effects associated with peropheral dopamine

Question 17

How is dopamine broken down at the synapse?

Answer 17

By monoamine oxidase (MAO) or COMT to make homovanillic acid (HVA)

Question 18

How can monoamine oxidase-B inhibition be used to treat Parkinsons?

Answer 18

Seregiline/Rasagiline

• Selectivity for MAO-B limits peripheral side effects
• Increases interneuronal dopamine levels
• Can be used as early monotherapies to increase time before L-DOPA or administered in combination

Question 19

How can inhibition of COMT be used to treat Parkinsons?

Answer 19

• Talcapone crosses BBB, inhibits COMT which breaks down dopamine and L-Dopa
• Used in combination with L-DOPA and carbidopa and reduces on-off effect by reducing fluctuations inn L_DOPA levels

Question 20

How can D2 dopamine receptor agonists be used to treat Parkinsons?

Answer 20

• Bromocriptine is a potent D2 agonist, however has a long plasma half life (6/8 hours) and so is administered less frequently
• Lisuride is a D1/D2 agonist which is more potent but shorter acting
  Both used as early monotherapies or in combination, similar side effects to high L-DOPA levels

Question 21

What is apomorphine?

Answer 21

• Relatively non-selective DA receptor agonist
• Due to emitic properties (vomiting) and short half-life administered subcutaneously
• Rapid effect in 3-20mins with brief duration, used to combat sudden attacks