Dyskinesia – Advances in Understanding the Pathophysiology and Treatment Options

a general effect of L-DOPA treatment. This article will provide a summary of the most important findings from these experimental models and their impact on the search for novel therapeutic options for LID.

Maladaptive Plasticity in L-DOPA-induced Dyskinesia Pre-synaptic Plasticity

Generally, therapeutic doses of L-DOPA given to rodent or primate models of PD typically require a substantial dopaminergic depletion before LID can be established. Even so, some animals with extensive dopamine denervation remain non-dyskinetic after chronic L-DOPA treatment. Therefore, the extent of LID cannot be solely predicted by the degree or pattern of dopaminergic depletion.17 Dopaminergic depletion is a significant risk factor but additional, thus far undetermined factors, must also be key to the development of LID.

Large and rapid fluctuations in extracellular levels of dopamine have been regarded as the prime trigger of the motor complications associated with L-DOPA therapy.18

Accordingly, recent positron

emission tomography studies in PD patients have demonstrated large increases in putaminal dopamine release after L-DOPA administration, which correlate positively with the severity of dyskinesia.19,20

In line with the clinical findings, high striatal levels of dopamine have been reported in L-DOPA-treated dyskinetic rats.21–23

The

fluctuations were originally thought to be due to the loss of dopamine neurons. However, more recently it has been suggested that a reduced expression/dysfunction of the dopamine transporter in the remaining nigrostriatal terminals21,24 serotonergic fibres25 dopamine levels.

and a higher density of striatal may be critical contributors to changes in

As the number of dopaminergic neurons decreases, the ability of the remaining terminals to convert L-DOPA into dopamine is reduced. Eventually, serotonergic neurons become the main site of L-DOPA decarboxylation in the brain. The lack of both dopamine autoreceptors and high-affinity reuptake capacity for dopamine, however, provides a source of unregulated dopamine efflux following exogenous L-DOPA administration.17

A causal link between the serotonin system and LID has recently been demonstrated in which LID was abolished by lesions of ascending 5-HT projections and greatly reduced by agonists of the serotonin autoreceptors 5-HT1A and 5-HT1B.26

Clinical trials with the 5-HT1A agonist sarizotan have demonstrated some improvements in dyskinesia, although the dopamine antagonist activity of this drug may have influenced the overall unimpressive clinical outcome.27,28

blunt the surge of striatal extracellular dopamine following L-DOPA administration.22

Pardoprunox (SLV308) is

also being evaluated as a 5HT1A agonist with additional dopamine D2/3-receptor partial agonist activity. It has already shown some success as a de novo treatment in early PD.29

As these pulsatile events are closely correlated with LID, current pharmaceutical strategy has moved towards the concept of continuous dopaminergic stimulation (CDS). CDS aims to prolong

Dysregulated dopamine release may contribute substantially to the pulsatile levels of dopamine caused by intermittent L-DOPA administration.18

EUROPEAN NEUROLOGICAL REVIEW

The delivery of CDS moved forward significantly with the introduction of devices such as the duodenal L-DOPA pump (DuoDopa) and dopamine receptor-agonist patches. New gene therapy approaches should also assist in this endeavour, utilising viral vector-mediated delivery of coding sequences for essential enzymes in the synthesis of dopamine.33

The enzymes involved are tyrosine

hydroxylase, the rate-limiting enzyme in dopamine synthesis, L-amino acid decarboxylase, which converts L-DOPA into dopamine, and guanosine 5’-triphosphate cyclohydrolase 1, which synthesises

35

Abnormal firing patterns in GPi/SNr

DBS

GABA dyn

D1 rec

Fluctuating dopamine (DA) (filled blue circles) levels after peripheral L-DOPA administration are considered the prime trigger of L-DOPA-induced dyskinesia (LID). Both unregulated DA release from serotonergic neurons and increased blood–brain barrier permeability may further exacerbate these fluctuating levels of DA. The expression of LID is also associated with an overactive signalling in cortical motor areas as well as supersensitised D1 dopamine receptors (D1 rec), causing abnormal signalling in striatal medium spiny neurons (MSNs) and long-term alternations in gene and protein expression. Overactive γ-Aminobutyric acid (GABA)ergic projections from striatum to the output nuclei of the basal ganglia leads to a large amount of GABA (green circles) being released in the output structures following L- DOPA administration. This neurochemical imbalance gives rise to abnormal firing patterns in GPi/SNr, which most likely represent the neural code for dyskinesia. DBS = deep brain stimulation; GPi = globus pallidus interna; SNr = substantia nigra pars reticulata.

These drugs were later found to

but two meta-analyses suggest that the consequence is significantly worse dyskinesia.31,32

the effects of L-DOPA, with the dual benefit of increases in ‘on-time’ and (hopefully) a reduction in dyskinesia. This approach is reportedly successful with the use of slow-release formulations of L-DOPA and adjuvant catechol-o-methyltransferase inhibitors improving ‘on’ time30

Figure 1: Pathophysiological Findings in L-DOPA-induced Dyskinesia and New Pharmacological Targets and Strategies Under Investigation

Cortex Overactive signalling

Striatum Glutamate

Large intermittent surges of extracellular DA

Angiostatic treatment 5-HT autoreceptor agonists Continuous dopamine stimulation

Abnormal signaling in striatal MSNs

Glutamatergic antagonists Non-dopaminergic agonists/ antagonists. Inhibitors of specific intracellular pathways

Gene transcription changes

AMPA rec NMDA rec mGluR5 5-HT axon

Dopamine D1 rec DA axon

capillary

GPi/SNr Capillary