Levidopa induced dyskinesia

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Describe LID
Hyperkinetic involunary uncontrolled movements
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How many patients get LID
2/3rd after 5 years
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What is the key factor related to levidopa
pulsatile recetpor stimulation. Less dyskinesia is seen with long acting DA agonists
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What peptide is increased in the direct pathway in dyskinesia
dynorphin
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What peptide is increased in the indirect pathway in dyskinesia
enkephalin
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Which pathway is overactive and which is underactive in PD
OVERACTIVE = direct. UNDERACTIVE = indirect
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A study that showed more dynorphin in a dyskinetic striatum
Henry, 2003
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Where is enkephalin released in the indirect pathway
In the GPe - coreleased with GABA from striatal neurons
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What receptor do they act on?
Presynaptic delta opioid receptors
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The effects of enkephalinase binding
reduces gaba release
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How does this affect the GPe neurons projecting to the STN
There is a loss of inhibition, so there is a large amount inhibition of STN neurons
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The consequences of STN neurons becoming inhibited
less glu input to the GPi, which means less inhibition of the thalamocortical tract
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Result of less inhibition of the thalamocortical tract
excessive thalamocortical feedback resulting in hyperkinesia
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Where is dynorphin released in the direct pathway
the striatal neurons projecting to the Gpi/SNr.
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Where does dynorphin act?
on mu and delta opioid receptors, on glutamatergic neurons projecting from the STN
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The effect of this mu and delta receptor activation
reduction in glut release.
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The effect of this glut release
less inhibition from Gpi-thalamus neurons, which means excessive thalamocortical feedback.
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Drug approaches to lessening LID
Giving long acting DA2 agonists, eg, ropinirole. OR given MAO-B inhibitors
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How is ropinirole used in the clinic
given as a first line treatment, or can be given as an adjucnt to LDOPA
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What is seen in the brain of LADA treated animals
Normal levels of dynorphin, enkephalin
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Why are MAO-B inhbitors referred to as LDOPA sparing
You don't need as big a dose of LDOPA because it keeps dopamine around for longer, so reduction of fluctuations
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Another way of preventing LID
Long acting formulation of LDOPA - duodenal pump that infuses ldopa directly
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Alternative non-DA approaches to dyskinesia
Opioid antagonists and glu based strategies
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problems with opioid antagonist
They work in animal models - but failed clinical trials. they also caused dysphoria.
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How is glutamate transmission disrupted in PD?
INCREASED glutamatergic transmission between cortex and striatum, (probably turning on gene expression of peptides).
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Examples of receptors on the corticostriatal synapses that could be targetted
mGlu2/3 presynaptically, post synaptic mGlu5, AMPA, NMDA
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A successful drug for LID
NMDA receptor antagonist AMANTIDINE. 2/3rds of patients ,so not ALL
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Another action of NMDA antagoninst amanditine
decreased expression of peptides
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Why are we looking for other treatments?
Doesn't help all - and it has cognitive side effects
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What NMDA receptor is localised to the striatum
NR2B,
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A drug that was trialed to antagonise NR2B
CP 101 606 - STILL gave cognitive side effects
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Example of an AMPA antagonist
Topiramate. - Promising in animals, failed in clinical trials. Got worse.
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An important feature of antidyskinesic drugs
Not reducing the effects of LDOPA.
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An example of an mGlu5 antagonist
MTEP - BUT slightly reduces LDOPA effectiveness. looking very promising though
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Do mglu5 affect peptide levels
yes, they reduce peptide mRNA expression
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How many patients get LID

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2/3rd after 5 years

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What is the key factor related to levidopa

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What peptide is increased in the direct pathway in dyskinesia

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What peptide is increased in the indirect pathway in dyskinesia

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