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Pharmacology 3 > L21: Parkinson's Disease > Flashcards

L21: Parkinson's Disease Flashcards

1
Q

What are the symptoms of Parkinson’s disease?

A
  • tremor at rest
  • abnormal posture
  • bradykinesia (slow initiation of movements)
  • Muscle rigidity (resistance to movement)
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2
Q

What are the signs of Parkinson’s disease?

A
  • shuffling gait (a type of walking, dragging one’s foot)
  • inability to perform skilled tasks
  • blank facial expression
  • speech impairment
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3
Q

What are the non-motor symptoms of Parkinson’s disease?

A
  • impulse control disorders are present in 15% of patients (include: pathological gambling, compulsive shopping, hypersexuality and binge-eating)
  • dementia occurs in more than 80% of patients with Parkinson’s disease after 20 years of disease duration
  • major non-motor neuropsychiatric symptoms include: depression, anxiety, apathy and psychosis
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4
Q

How is voluntary movement controlled?

A
  • Voluntary movement is controlled by signals from the cortex that travel down the pyramidal tracts to initiate motoneurone activity.
  • These signals are fine-tuned by influences from extrapyramidal regions, e.g. the basal ganglia (smooth coordinated movements)
  • Parkinson’s disease is associated with dysfunction of the basal ganglia
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5
Q

What are the parts of the basal ganglia involved in movement control?

A
  • thalamus
  • substantia nigra: reticulata (SNpr) or compacta (SNpc)
  • striatum: caudate nucleus; caudate putamen
  • globus pallidus: externa (GPe) or interna (GPi)
  • subthalamic nucleus (STN)
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6
Q

To what events in the brain is Parkinson’s disease associated ?

A

PD is associated with degeneration of dopamine-containing cells in the substantia nigra of the basal ganglia

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7
Q

At what point are symptoms of Parkinson’s disease observed? How long does it take for it to appear?

A

Symptoms of PD occur only after >70% of the nigrostriatal dopamine content is lost. This is estimated to take 8 years or more from onset of degeneration.

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8
Q

What is the mechanism of normal function of the basal ganglia?

A

SEE L21, slide 9 for diagramm
- motor signal originates in cortex
- cortex excites striatum by glutamate
- direct pathway inhibits GPi / SNr (output nuclei) via D1 receptor and GABA, facilitating transmission to thalamus
- indirect pathway acts on GPe which acts on STN, inhibiting transmission
- STN acts on GPi / SNr (output nuclei)
- GPi / SNr (output nuclei) inhibit thalamus via GABA, therefore thalamus signals are modified

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9
Q

What is the output of basal ganglia? What does it do?

A

Basal ganglia output is via the GPi / SNr and mediates tonic inhibition of the thalamo-cortical motor pathway.

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10
Q

What and how is GPi / SNr output regulated?

A

Striatum modulates GPi / SNr output via:
- direct pathway: inhibitory, GABA
- indirect pathway. STN, excitatory, glutamate

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11
Q

What is the function of dopamine in the basal ganglia?

A
  • facilitates transmission along the direct pathway through D1 receptors
  • inhibits transmission along the indirect pathway through D2 receptors
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12
Q

What happens to the function of basal ganglia in Parkinson’s disease?

A
  • activity of GPe is completely inhibited in indirect pathway
  • excitatory signal from STN is increased, so GPi / SNr is stimulated more
  • inhibition of GPi / SNr through direct pathway is reduced
  • this stimulation of GPi / SNr increases inhibition of Thalamus, meaning that it doesn’t send back the signal

In summary:
- inhibition of GPi / SNr output by the direct pathway is reduced
- excitation of the GPi / SNr by the indirect pathway is increased

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13
Q

What is the main drug that facilitates dopaminergic neurotransmission in treatment of Parkinson’s disease?

A

L-dopa, as it is already and intermediate, this facilitates synthesis and release of endogenous dopamine.
L-dopa can cross the BBB where it can be converted to dopamine by L-dopa decarboxylase

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14
Q

Why cannot dopamine directly be administered for patients of Parkinson’s disease?

A

Dopamine cannot cross the blood-brain barrier.

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15
Q

What is the efficiency of L-DOPA?

A

Only 1% of the oral L-dopa gets to the brain because of peripheral metabolism.

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16
Q

How can efficiency of L-DOPA be increased in treatment of Parkinson’s disease?

A

L-dopa can be combined with inhibitors of peripheral metabolism to allow lower and less frequent doses to be used.

17
Q

What are the dopa decarboxylase inhibitors? Give examples

A
  • Inhibit peripheral metabolism of L-DOPA.
  • Examples: carbidopa, benserazide
    Carbidopa does not cross the BBB
18
Q

What are the unwanted effects of L-dopa therapy of Parkinson’s disease patients?

A

L-dopa induces dyskinesia - involuntary writhing movements.

19
Q

What is the explanation of L-dopa-induced dyskinesia (writhing movements)

A

Levels of inhibitory GABA in direct pathway, which act on GPi / SNr are too high. This leads to excessive inhibition of GPi / SNr, less inhibition to thalamus, meaning that it gets excited more and has a stronger effect on the cortex.

20
Q

What is the on-off effect associated with L-dopa therapy?

A

After a few years of L-DOPA therapy, patients randomly freeze and cannot move. Reasons are not known, but it’s related to time of L-dopa therapy start, so it’s delayed as much as possible.

21
Q

What are other drugs used for treatment of Parkinson’s disease alone or as adjuncts to L-DOPA therapy? What’s their mechanism of action?

A
  • selegiline or rasagiline inhibit MAO-B in the brain, which breaks down dopamine in the brain, so the action is prolonged
  • entacapone or tolcapone inhibit CoMT, which increases the effectiveness of L-dopa therapy
  • Bromocriptine, pergolide, apomorphine as direct acting dopaminergic agonists for D1/D2 receptors
  • Pramipexole, ropinirole, rotigotine as direct acting dopaminergic agonists for D2/D3 receptors

CHECK L21, slides 22-25 for diagramms

22
Q

What are the genetic causes for Parkinson’s disease?

A

Directly related to mutations:
- UCHL1 gene - protein in Lewy bodies, polymorphisms associated with sporadic PD
- SNCA gene - alpha-synuclein in Lewy bodies
- PARK2 gene - Lewy bodies and tau pathology
- LRRK2 gene - Lewy bodies and NFT pathology

The link between sporadic PD and environmental influences is now widely believed to reflect an interaction with genetic risk factors.

CHECK L21, slide 28 for table

23
Q

What is the “Oxidative Stress” theory regarding disease pathway in Parkinson’s disease?

A

Postmortem evidence for mitochondrial impairment
Oxidative Stress (not enough ATP produced) refers to the excessive production of “reactive oxygen species” (ROS), e.g. H2O2, oxygen and hydroxyl free radicals, when oxidative phosphorylation is compromised (Builds up and causes damage).
ROS damage important intracellular components such as DNA, enzymes and membrane lipids
MPTP doesn’t cause Parkinson’s disease, but cause symptoms (check L21, slide 30 for diagramm)

24
Q

What are Lewy bodies? How are they related to Parkinson’s disease?

A

PD is associated with the appearance of spherical deposits in cells of the substantia nigra and brainstem called Lewy bodies (in short: aggregates of protein)

25
Q

What is alpha-synuclein? What is its function? How is it related to Parkinson’s disease?

A
  • Main function is to control neurotransmitter release.
  • Aggregates of alpha-synuclein promote defective endosomal trafficking particularly at neuronal synapses.
  • Disrupted dopamine uptake into vesicles could lead to high cytoplasmic dopamine.
  • Oxidative stress and the production of free radicals.
  • Neuronal death.
26
Q

Why are Dopaminergic Substantia Nigra compacta (SNc) neurones particularly vulnerable to degeneration in PD?

A

Two factors to contribute hypothesized:
- Calcium entry during autonomous pace-making of DA SNc neurones. (Cells don’t like calcium in cytoplasm, a lot of energy needed to pack the vesicles). Cytosolic Ca2+ is only weakly buffered by endogenous proteins, which means there is a high metabolic demand placed on mitochondrial oxidative phosphorylation by Ca2+ATPases.
- DA SNc neurones have massive, complex, unmyelinated axonal harbours. High energetic cost of action potential propagation also places metabolic demands

Both place high metabolic demands on mitochondrial oxidative phosphorylation. Thus, reserve capacity is limited; any additional demands lead to oxidative stress

Pharmacology 3 (21 decks)

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