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Neuroanatomy and neurodegenerative disorders > Therapeutic targets for PD > Flashcards

Therapeutic targets for PD Flashcards

1
Q

Where are large DA concentrations found?

A

Corpus striatum, limbic system and hypothalamus

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2
Q

How is dopamine synthesised?

A

From tyrosine to dopa (via tyrosine hydroxylase) followed by decarboxylation to form dopamine (via DOPA decarboxylase)

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3
Q

What substances metabolise dopamine and what are the main products?

A

MAO-B and COMT metabolise dopamine into DOPAC and HVA (homovanillate) respectively

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4
Q

There are 2 major classes of DA receptors. What does activation of D1 receptors do and what G-protein is it coupled to?

A
  • Stimulates adenylyl cyclase to produce cyclic AMP
  • Coupled to Gs
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5
Q

What does activation of D2 receptors do and what G-protein is it coupled to?

A
  • Inhibits adenylyl cyclase activity
  • Coupled to Gi
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6
Q

There are 5 subtypes of DA receptor. Which subtypes belong to which receptor?

A
  • D1 - D1 and D5 receptors
  • D2 - D2, D3 and D4 receptors
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7
Q

Which DA receptor subtypes are expressed presynaptically?

A

D2 and D3

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8
Q

Which DA receptor regulates dopamine release?

A

D3 autoreceptors - when activated they inhibit DA release

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9
Q

Which DA receptor regulates DA metabolism and biosynthesis?

A

D2 autoreceptors

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10
Q

What is the main role and effect of D1 and D5 receptor activation?

A

Increase cAMP –> Post-synaptic inhibition

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11
Q

What is the main role and effect of D2, D3 and D4 receptor activation?

A

Decrease cAMP –> pre- and post-synaptic inhibition

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12
Q

What are the 3 main dopamine pathways in the brain?

A

Nigrostriatal, mesolimbicocortical and tuberohypophyseal

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13
Q

What is the nigrostriatal pathway involved in?

A

Motor control

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14
Q

What is the mesolimbicocortical pathway involved in?

A

Emotion and reward systems

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15
Q

What is the tuberohypophyseal pathway involved in?

A

Endocrine control

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16
Q

Where does the nigrostriatal pathway start and end?

A

Substantia nigra (midbrain) –> corpus striatum

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17
Q

Where does the mesolimbicocortical pathway start and end?

A

Ventral tegmental area (midbrain) –> limbic system, cerebral cortex and striatum

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18
Q

Where does the tuberohypophyseal pathway start and end?

A

Periventricular area (hypothalamus) –> Infundibulum, median eminence of anterior pituitary

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19
Q

Where does the direct pathway start and finish?

A

Substantia nigra –> striatum

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20
Q

Where does the indirect pathway start and finish?

A

Striatum –> globus pallidus

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21
Q

Does the direct pathway have an inhibitory or disinhibitory effect on BG output?

A

Inhibitory

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22
Q

Does the indirect pathway have an inhibitory or disinhibitory effect on BG output?

A

Disinhibitory

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23
Q

Direct pathway - in the striatum, dopamine acts on D1 receptors, which has what kind of effect on dynorphin-containing medium spiny neurons?

A

Excitatory effect

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24
Q

Indirect pathway - in the striatum DA also acts on D2 receptors expressed on enkephalin containing striatal neurons, which results in …?

A

Inhibition

25
Q

Lack of DA in PD reduces activation of striatal D1 and D2 receptors which results in …?

A
  • Reduced inhibition in indirect pathway
  • Decreased excitation in direct pathway
  • Net result = excessive excitation of GPi-SNpr complex and over inhibition of thalamocortical centres
26
Q

What do most current PD therapies aim to achieve?

A

Aim to boost DA signalling in the striatum

27
Q

How could drugs boost dopamine signalling?

A
  • Increased production of endogenous DA
  • Drugs that mimic dopamine action
  • Drugs that prevent degradation of endogenous (MAO-B inhibitors) or exogenous DA (COMT inhibitors)
28
Q

Why does levodopa (DA precursor) have to be combined with a dopa deecarboxylase inhibitor (e.g. carbidopa)?

A

To reduce dose needed and to reduce peripheral side effects

29
Q

How do decarboxylase inhibitors work with levodopa in the periphery?

A

Prevents levodopa conversion to dopamine

30
Q

How do decarboxylase inhibitors (COMTI) work with levodopa in the brain?

A

Decarboxylase inhibitors cannot cross the BBB and thus decarboxylation of levodopa to dopamine occurs rapidly

31
Q

How effective is levodopa?

A
  • At start of treatment 80% of patients show improved motor function and 20% show complete restoration of motor function.
  • Effectiveness declines over time
32
Q

What are the possible reasons for decline in effectiveness of levodopa?

A
  • Natural progression of disease
  • Receptor downregulation
33
Q

What are some of the most common acute side effects of levodopa?

A
  • Nausea, anorexia, hypotension, hallucinations, delusions
  • Mesolimbic system is affected by levodopa, causing overexcitation –> schizophrenia symptoms
34
Q

What are some of the slowly developing side effects of levodopa as PD progresses?

A
  • Dyskinesia - involuntary writhing movements of the face and limbs (usually start within 2 years)
  • On-off effect - rapid fluctuations in clinical state
35
Q

How are the long-term side effects of levodopa being counteracted in ongoing research?

A

Levodopa is usually taken once per day but taking smaller doses more often is being researched to reduce occurrence of on-off responses

36
Q

What do MAO-inhibitors e.g. selegiline do?

A
  • Block DA metabolism thus increasing endogenous DA levels
  • Bonus - they don’t cause peripheral side effects due to specificity in the brain
37
Q

What do DA receptors agonists do and what are some examples of these drugs?

A
  • Selective D2 receptors agonists produce consistent anti-parkinsonian effects, whereas D1 receptor agonsits may produce a broader range of effects.
  • Bromocriptine (D2R agonsit) - longer duration of action than levodopa
  • Apomorphine
  • Lisuride
  • Pergolide (D1/D2 agonist)
38
Q

Why can muscarinic antagonists be used in PD?

A
  • They increase DA concentrations at DA receptors in striatum
  • Antagonise the action of ACh at ACh receptors in the striatum
39
Q

What is the mechanism of action of acetylcholine antagonists such as benztropine?

A
  • Suppression of inhibitiory effect on striatal neurons
  • Suppression of presynaptic inhibition of DA release from nerve terminals
  • Thus increasing DA levels
40
Q

What are some of the limitations of muscarinic antagonists?

A
  • They reduce tremor more than rigidity/hypokinesia
  • Side effects - dry mouth, constipation, impaired vision, urinary retention
  • Mainly used for parkinsonism induced by anti-psychotics
41
Q

Why do adenosine A2A receptor antagonists have therapeutic potential in PD?

A
  • Adenosine A2Ar are enriched in the striatum.
  • High levels are expressed on D2 receptor expressing GABAergic striatal neurons.
  • Activation of A2Ars opposes effects of D2rs by decreasing affinity for DA for D2rs activating signalling cascades that D2rs inhibit
  • A2Ar antagonists would be expected to enhance effects of DA on striatal neurons
42
Q

What is another advantage of A2A receptor antagonists (other than enhancing effects of DA on striatal neurons)?

A
  • Neuroprotective action
  • Caffeine is an AR antagonists and has been shown to protect against DA neuron toxicity
43
Q

What are some of the caveats of using A2A receptor antagonists for PD?

A

Ischaemic tissue damage, pro-inflammatory, psychosis, insomnia

44
Q

How is neural transplantation proposed to work in PD and is it effective?

A
  • Injection of midbrain neurons from fetal cells into the substantia nigra pars compacta to replace damaged cells.
  • Has been shown to maintain function and improve symptoms for up to 15 years in some patients but use of fetal tissue is not sustainable
45
Q

What types of stem cells could be used to generate dopaminergic neurons?

A
  • Embryonic stem cells - easily differentiate into neurons compared to other cell types
  • Induced pluripotent stem cells - can be generated in large numbers and differentiated into DA neurons for transplantation
46
Q

What are some of the caveats with using stem cells in PD?

A
  • Tumour formation due to still dividing cells
  • Tissue rejection
  • Robust and safe cells that can survive and function are difficult to generate
47
Q

When would deep brain stimulation be used in PD?

A

Patients with intractable tremor, or who are affected by long-term complications of levodopa

48
Q

Which areas are targeted in deep brain stimulation?

A

Subthalamic nucleus and globus pallidus (internal segment) - STN stimulation is superior to GPi as it produces a more pronounced anti-akinetic response

49
Q

Describe the procedure of DBS

A
  • DBS microelectrode is connected to a programmable stimulator/battery that is implanted in the chest in the sub-clavicular space
  • Patient is kept conscious to allow the surgeon to identify if the tremor disappears
50
Q

What are some of the benefits of DBS?

A
  • Better control of motor symptoms for a longer period of time than medication alone.
  • Increase time spent in an ‘on’ state each day - thus dose of PD drugs can be reduced –> leading to reduced side effects.
  • Some relief from non-motor symptoms e.g. insomnia and pain.
  • Can increase QOL by 18-30% over drug and behavioural therapies alone
51
Q

What are some of the short term side effects of DBC?

A
  • Due to stimulation current spreading to non-target brain regions
  • Tingling, pins and needles, problems articulating words, dizziness, balance problems and falls.
  • These should all disappear completely when the current is reduced/stopped
52
Q

What are some of the long-term side effects of DBS?

A
  • Loss of battery strength
  • Electrodes or extension leads break
  • Depression and apathy
53
Q

What are some other surgical procedures used in PD?

A

Lesioning surgery:

  • Thalamotomy
  • Pallidotomy
  • Subthalamotomy
54
Q

What is involved in a pallidotomy and what are its benefits?

A
  • Most common type of lesioning surgery and it targets the globus pallidus internal segment.
  • Can lead to relief of tremor, rigidity, bradykinesia, motor fluctuations and dyskinesia
55
Q

How does gene therapy work in PD?

A

Uses viral vectors to introduce a protein of interest into a specific brain region

56
Q

How do viral vectors reach the brain?

A
  • A tube about the width of a hair is inserted through the brain to the STN where the virus is injected.
  • The virus enters a brain cell and delivers a gene that prompts the cell to create a substance called glutamic acid decarboxylase or GAD
57
Q

What is the role of GAD in gene therapy for PD?

A
  • GAD is the key enzyme that synthesises the major inhibitory neurotransmitter, GABA.
  • In PD the STN is disinhibited resulting in pathological overexcitation of its targets (GPi and SNpr).
  • In turn increased GPi/SNpr outflow is thought to underlie tremor, rigidity and bradykinesia.
  • Production of GABA in STN will alleviate these symptoms by inhibiting STN activity
58
Q

What is another target for gene therapy?

A
  • GDNF is a growth factor that promotes DA neuron survival and regeneration in rodent and primate PD models
  • Success using this approach in humans has been highly variable
59
Q

What are some of the potential problems with gene therapy?

A
  • Short-term - patients must undergo treatment every few months
  • Immunological response - immune system can identify and destroy viral vector
  • Toxicity - viral vector may mutate and become pathogenic

Neuroanatomy and neurodegenerative disorders (7 decks)

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