Levidopa induced dyskinesia 0.0 / 5 ? BiologyParkinson'sUniversityAll boards Created by: Annabel ForsdykeCreated on: 28-04-16 16:14 Describe LID Hyperkinetic involunary uncontrolled movements 1 of 35 How many patients get LID 2/3rd after 5 years 2 of 35 What is the key factor related to levidopa pulsatile recetpor stimulation. Less dyskinesia is seen with long acting DA agonists 3 of 35 What peptide is increased in the direct pathway in dyskinesia dynorphin 4 of 35 What peptide is increased in the indirect pathway in dyskinesia enkephalin 5 of 35 Which pathway is overactive and which is underactive in PD OVERACTIVE = direct. UNDERACTIVE = indirect 6 of 35 A study that showed more dynorphin in a dyskinetic striatum Henry, 2003 7 of 35 Where is enkephalin released in the indirect pathway In the GPe - coreleased with GABA from striatal neurons 8 of 35 What receptor do they act on? Presynaptic delta opioid receptors 9 of 35 The effects of enkephalinase binding reduces gaba release 10 of 35 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 11 of 35 The consequences of STN neurons becoming inhibited less glu input to the GPi, which means less inhibition of the thalamocortical tract 12 of 35 Result of less inhibition of the thalamocortical tract excessive thalamocortical feedback resulting in hyperkinesia 13 of 35 Where is dynorphin released in the direct pathway the striatal neurons projecting to the Gpi/SNr. 14 of 35 Where does dynorphin act? on mu and delta opioid receptors, on glutamatergic neurons projecting from the STN 15 of 35 The effect of this mu and delta receptor activation reduction in glut release. 16 of 35 The effect of this glut release less inhibition from Gpi-thalamus neurons, which means excessive thalamocortical feedback. 17 of 35 Drug approaches to lessening LID Giving long acting DA2 agonists, eg, ropinirole. OR given MAO-B inhibitors 18 of 35 How is ropinirole used in the clinic given as a first line treatment, or can be given as an adjucnt to LDOPA 19 of 35 What is seen in the brain of LADA treated animals Normal levels of dynorphin, enkephalin 20 of 35 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 21 of 35 Another way of preventing LID Long acting formulation of LDOPA - duodenal pump that infuses ldopa directly 22 of 35 Alternative non-DA approaches to dyskinesia Opioid antagonists and glu based strategies 23 of 35 problems with opioid antagonist They work in animal models - but failed clinical trials. they also caused dysphoria. 24 of 35 How is glutamate transmission disrupted in PD? INCREASED glutamatergic transmission between cortex and striatum, (probably turning on gene expression of peptides). 25 of 35 Examples of receptors on the corticostriatal synapses that could be targetted mGlu2/3 presynaptically, post synaptic mGlu5, AMPA, NMDA 26 of 35 A successful drug for LID NMDA receptor antagonist AMANTIDINE. 2/3rds of patients ,so not ALL 27 of 35 Another action of NMDA antagoninst amanditine decreased expression of peptides 28 of 35 Why are we looking for other treatments? Doesn't help all - and it has cognitive side effects 29 of 35 What NMDA receptor is localised to the striatum NR2B, 30 of 35 A drug that was trialed to antagonise NR2B CP 101 606 - STILL gave cognitive side effects 31 of 35 Example of an AMPA antagonist Topiramate. - Promising in animals, failed in clinical trials. Got worse. 32 of 35 An important feature of antidyskinesic drugs Not reducing the effects of LDOPA. 33 of 35 An example of an mGlu5 antagonist MTEP - BUT slightly reduces LDOPA effectiveness. looking very promising though 34 of 35 Do mglu5 affect peptide levels yes, they reduce peptide mRNA expression 35 of 35
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