Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How is dopamine synthesised?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Which DA receptor subtypes are expressed presynaptically?

A

D2 and D3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Which DA receptor regulates dopamine release?

A

D3 autoreceptors - when activated they inhibit DA release

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Which DA receptor regulates DA metabolism and biosynthesis?

A

D2 autoreceptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

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

A

Increase cAMP –> Post-synaptic inhibition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

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

A

Decrease cAMP –> pre- and post-synaptic inhibition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are the 3 main dopamine pathways in the brain?

A

Nigrostriatal, mesolimbicocortical and tuberohypophyseal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the nigrostriatal pathway involved in?

A

Motor control

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the mesolimbicocortical pathway involved in?

A

Emotion and reward systems

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is the tuberohypophyseal pathway involved in?

A

Endocrine control

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Where does the nigrostriatal pathway start and end?

A

Substantia nigra (midbrain) –> corpus striatum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Where does the mesolimbicocortical pathway start and end?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Where does the tuberohypophyseal pathway start and end?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Where does the direct pathway start and finish?

A

Substantia nigra –> striatum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Where does the indirect pathway start and finish?

A

Striatum –> globus pallidus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

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

A

Inhibitory

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

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

A

Disinhibitory

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
Lack of DA in PD reduces activation of striatal D1 and D2 receptors which results in ...?
* 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
What do most current PD therapies aim to achieve?
Aim to boost DA signalling in the striatum
27
How could drugs boost dopamine signalling?
* 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
Why does levodopa (DA precursor) have to be combined with a dopa deecarboxylase inhibitor (e.g. carbidopa)?
To reduce dose needed and to reduce peripheral side effects
29
How do decarboxylase inhibitors work with levodopa in the periphery?
Prevents levodopa conversion to dopamine
30
How do decarboxylase inhibitors (COMTI) work with levodopa in the brain?
Decarboxylase inhibitors cannot cross the BBB and thus decarboxylation of levodopa to dopamine occurs rapidly
31
How effective is levodopa?
* At start of treatment 80% of patients show improved motor function and 20% show complete restoration of motor function. * Effectiveness declines over time
32
What are the possible reasons for decline in effectiveness of levodopa?
* Natural progression of disease * Receptor downregulation
33
What are some of the most common acute side effects of levodopa?
* Nausea, anorexia, hypotension, hallucinations, delusions * Mesolimbic system is affected by levodopa, causing overexcitation --\> schizophrenia symptoms
34
What are some of the slowly developing side effects of levodopa as PD progresses?
* Dyskinesia - involuntary writhing movements of the face and limbs (usually start within 2 years) * On-off effect - rapid fluctuations in clinical state
35
How are the long-term side effects of levodopa being counteracted in ongoing research?
Levodopa is usually taken once per day but taking smaller doses more often is being researched to reduce occurrence of on-off responses
36
What do MAO-inhibitors e.g. selegiline do?
* Block DA metabolism thus increasing endogenous DA levels * Bonus - they don't cause peripheral side effects due to specificity in the brain
37
What do DA receptors agonists do and what are some examples of these drugs?
* 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
Why can muscarinic antagonists be used in PD?
* They increase DA concentrations at DA receptors in striatum * Antagonise the action of ACh at ACh receptors in the striatum
39
What is the mechanism of action of acetylcholine antagonists such as benztropine?
* Suppression of inhibitiory effect on striatal neurons * Suppression of presynaptic inhibition of DA release from nerve terminals * Thus increasing DA levels
40
What are some of the limitations of muscarinic antagonists?
* 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
Why do adenosine A2A receptor antagonists have therapeutic potential in PD?
* 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
What is another advantage of A2A receptor antagonists (other than enhancing effects of DA on striatal neurons)?
* Neuroprotective action * Caffeine is an AR antagonists and has been shown to protect against DA neuron toxicity
43
What are some of the caveats of using A2A receptor antagonists for PD?
Ischaemic tissue damage, pro-inflammatory, psychosis, insomnia
44
How is neural transplantation proposed to work in PD and is it effective?
* 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
What types of stem cells could be used to generate dopaminergic neurons?
* 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
What are some of the caveats with using stem cells in PD?
* Tumour formation due to still dividing cells * Tissue rejection * Robust and safe cells that can survive and function are difficult to generate
47
When would deep brain stimulation be used in PD?
Patients with intractable tremor, or who are affected by long-term complications of levodopa
48
Which areas are targeted in deep brain stimulation?
Subthalamic nucleus and globus pallidus (internal segment) - STN stimulation is superior to GPi as it produces a more pronounced anti-akinetic response
49
Describe the procedure of DBS
* 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
What are some of the benefits of DBS?
* 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
What are some of the short term side effects of DBC?
* 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
What are some of the long-term side effects of DBS?
* Loss of battery strength * Electrodes or extension leads break * Depression and apathy
53
What are some other surgical procedures used in PD?
Lesioning surgery: * Thalamotomy * Pallidotomy * Subthalamotomy
54
What is involved in a pallidotomy and what are its benefits?
* 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
How does gene therapy work in PD?
Uses viral vectors to introduce a protein of interest into a specific brain region
56
How do viral vectors reach the brain?
* 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
What is the role of GAD in gene therapy for PD?
* 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
What is another target for gene therapy?
* 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
What are some of the potential problems with gene therapy?
* 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)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions