Tackling dyskinesia in PD Flashcards
Define leva-dopa induced dyskinesia
- Hyperkinetic involuntary uncontrolled movements (choreic or dystonic).
- Face and limbs mostly affected.
- Arise in over 2/3 patients after 5 years of L-dopa or some DA agonists
It is the pulsatile stimulation of dopamine receptors that seems to induce dyskinesias. Constant receptor activation results in less dsykinesia.
Alternative dopamine therapies with less dyskinesia
- Long acting Dopamine agonists
- MAO-B irreversible inhibitor
- Duodopa pump
Long acting Dopamine agonists
Ropinirole
If this is given as a first line of treatment then it reduces the risk and delays the onset of dyskinesia.
irreversible MAO-B inhibitor
selegiline
Increases endogeneous dopamine levels and reduces their fluctuations by decreasing their metabolism by MAO-B.
It is effective as a stand-alone therapy in early stages, and can be combined with L-DOPA (reducing required dose of L-DOPA) in later stages
Duodopa pump
This pump continuously infuses levadopa and carbidopa into the duodenum
However, it only prolongs the need for L-DOPA and there are no slow-release formulas. It reduces parkinsonism and shows less fluctuations/dyskinesia than L-DOPA
Treatments for leva-dopa induced dyskinesia
Glutamatergic antagonists
Amantidine is a weak NMDA antagonist that reduces dyskinesia intensity, suggesting that overactivity of glutamatergic inputs in the basal ganglia is involved in dyskinesia. Its use is limited by the emergence of cognitive side effects.
GluNR2B antaongists in development
AMPAR antagonist topiramate worked in MPTP primates but failed clinical trials
What makes L-dopa induced dyskinesias irreversible?
After their induction, the same involuntary movements will occur with every subsequent L-dopa administration.
The functioning of the basal ganglia and it’s response to drug administration has become fundamentally altered.
Once it has been established, it is equally promoted by L-dopa and dopamine agonists, but switching from pulsatile delivery to continuous can reverse its expression.
What are the two components of drug induced dyskinesias?
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Priming mechanisms.
These result from the loss of dopaminergic input from the nigra to the striatum, resulting in abnormalities in the glutamatergic synaptic connectivity in the striatum, giving rise to abnormal connectivity between the striatum and motor cortex. This gives rise to a disturbance in basal ganglia function, resulting in uncontrollable movements under dopamine therapy. -
Drug treatment
Against the background of pathological priming, drug treatment influences the rate and severity at which dyskinesias emerge. This process of induction is also dependent on priming mechanisms - the extent of degenaration regulates the level and duration of drug exposure that is required to induce dyskinesia. Normal humans and animals do not develop dyskinesias when they are chronically exposed to L-dopa.
Whichs structures comprise the basal ganglia?
The basal ganglia consist of 4 subthalamic nuclei:
- Substantia nigra
- Striatum (caudate nucleus and putamen)
- GPi and GPe
- Subthalamic nucleus (STN)
What role does the pharmacokinetic profile of dopaminergic therapies play in dsykinesia induction?
The plasma half life and the absorbtion profile alter dyskinesia induction.
For example, L-dopa has a short plasma half life, and is absorbed erratically from the gastrointestinal tract. This results in oscillations in plasma levels. In early stages of PD, where there is less degenaration, L-dopa is stored in the synaptic terminals - smoothing out the levels of dopaminergic activity in the striatum. However, as terminals are increasingly lost, the activity of L-dopa becomes shorter and fluctuates. This leads to the pulsatile stimulation of dopamine receptors that contributes to dyskinesia induction - as normal dopamine release is constant.
The differences in dopaminergic stimulation between L-dopa and other agonists contribute to their clinical differences but they do not explain priming, which is due to progressive nigral denervation and the effect of pulsatile dopamine receptor stimulation
What role may receptor selectivity play in drug induced dsykinesias?
Dopamine agonists are highly selective for D2 receptors, whereas L-dopa has affinity for both D1 and D2 receptors.
There is post mortem evidence of D1 upregulation in MPTP treated primates who exhibit L-dopa induced dsykinesias. However, as both dopamine agonists and L-dopa can result in execution of dyskinesias once established, a D1 related mechanism is more likely to underlie induction rather than expression.
How may altered transmission in the striatum lead to dyskinesia expression?
Degenaration of dopaminergic input results in reduced D1 and D2 receptor stimulation, leading to a loss of dopaminergic LTP/LTD (1, 2.) This results in a loss of integration of cortical glutamatergic input (3) to the striatal GABAergic neurons.This initially normalized by dopamine replacement therapy. (4.)
As the disease progresses, glutamatergic receptors change in number and distribution due to spine loss. This may be underpinned by alterations in scaffolding proteins that hold them together at the post synaptic density (5). Phosphorylation, which controls glutamates action on the cells is altered due to degeneration and L-dopa therapy.
All of these changes result in altered glutamatergic action at the synapse, altering signalling cascades and striatal output.
These lead to induction of dsykinesias.
What are the difficulties in identifying the mechanisms involved in dyskinesias?
The multiple changes in gene and protein expression that have been observed suggest that an entire network is altered as a result of loss of the nigrostriatal input, and that further compensatory alterations occur secondary to this and in response to the dyskinetic movements themselves.
What is thought to underlie striatal learning?
Activity dependent alterations (LTP/LTD) between corticostrial glutamatergic synapses formed on the spiny projection neurons (SPNs i.e., GABAergic striatal neurons). One of the most important modulators of these synapses is dopamine. The different expression of GPCRs on the direct and indrect pathway gives rise to differential action of dopamine.
D2 receptors in the iSPN (indirect) faciliates Hebbian LTD.
D1 receptors in the dSPN (direct) facilitates Hebbian LTP.
These synpases underlie normal learning, and their dsyregulation is implicated in movement disorders such as P.D.
What is the role of adensoine in cortical striatal learning?
A2a adensoine receptors mediates LTP in the iSPN, which is opposed by the LTD action of DA on the D2 receptors.
These two signalling pathways give rise to bidirectional control of adenylyl cyclase. D2 receptors couple to Gi proteins to inhibit adenylyl cyclase, where A2aR couple to G<strong>olf </strong> receptors (type of Gs protein) to stimulate adenylyl cyclase.
In the dSPN, D1 receptors promote LTP, but it is unclear whether there is a Gprotein that promotes LTD.
