Neurodegenerative Disease Parkinson’s Disease
Dyskinesia – Advances in the Understanding of Pathophysiology and Possible Treatment Options
Hanna S Lindgren,1 M Angela Cenci2 and Emma L Lane3 1. Postdoctoral Fellow, Brain Repair Group, School of Biosciences, Cardiff University;
2. Professor of Experimental Medical Science and Head, Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University; 3. Lecturer in Pharmacology, Welsh School of Pharmacy and Brain Repair Group, School of Biosciences, Cardiff University
Abstract
The degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease gives rise to tremor and slowness of movement, cardinal motor symptoms of the disease that can be alleviated by the dopamine precursor L-DOPA. Despite this, long-term L-DOPA treatment is hampered by the development of abnormal involuntary movements, i.e. dyskinesia, in the majority of patients. The pathophysiology of dyskinesia is complex and multifactorial, but excessive swings in extracellular dopamine causing aberrant plasticity in dopaminoceptive neurons are attributed a primary role. To date there are few effective treatment alternatives for patients with Parkinson’s disease experiencing dyskinesia, representing an unmet therapeutic need in the treatment strategy of the disease. This article reviews recent findings from both clinical and pre-clinical studies and their impact on the search for novel therapeutic approaches to levodopa-induced dyskinesia.
Keywords
L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine replacement therapy, dyskinesia, animal models, plasticity, basal ganglia, dopamine, serotonin, noradrenalin, glutamate
Disclosure: The authors have no conflicts of interest to declare. Received: 10 September 2010 Accepted: 4 November 2010 Citation: European Neurological Review, 2010;5(2):34–40 Correspondence: Emma L Lane, Brain Repair Centre, Department of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, Wales, UK. E:
Laneel@cf.ac.uk
Since its introduction in the 1960s, dopamine replacement therapy with its metabolic precursor L-3,4-dihydroxyphenylanaline (L-DOPA) has remained the most effective pharmacotherapy for Parkinson’s disease (PD).1
However, its utility is limited by the development of motor complications that become increasingly evident as the disease progresses. These include:
Particularly in early disease, it is efficiently converted into dopamine, replacing that which is lost through the degeneration of nigrostriatal dopaminergic neurons. In doing so, L-DOPA alleviates bradykinesia and rigidity, helping, for example, to restore gait and arm swing.2
• • • •
The development of ‘on-off’ fluctuations;
periods in which the beneficial effects of L-DOPA are rapidly lost; a reduction in the effective duration of L-DOPA response; and
the most troubling – choreic and dystonic abnormal involuntary movements, collectively termed L-DOPA-induced dyskinesia (LID).
The movements are present predominantly during the beneficial activity of L-DOPA,3
most commonly occurring as ‘peak dose’
dyskinesia but also occurring as dopamine levels decline as ‘end-of-dose’ LID. The reported incidence of LID varies between studies and patient groups, but can affect up to 40% of PD patients after only four to six years of L-DOPA therapy.4
Given that L-DOPA is still the most efficacious antiparkinsonian medication, providing therapy that circumvents LID remains a major unmet therapeutic need in the treatment strategy of PD. Currently, pharmacological interventions are limited to short-term
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treatment with the antiviral and weak NMDA (N-methyl-D-aspartic acid) antagonist amantadine or invasive neurosurgical intervention targeting the deep basal ganglia nuclei with deep brain stimulation (DBS). DBS stands alone as the only therapeutic option for severe LID and is both expensive and associated with acute and ongoing risks.5–7
The criteria for patient selection for this treatment is quite stringent and, critically, DBS is not offered to patients suffering from cognitive impairment, which affects as many as one-third of PD patients.8
Although the precise mechanisms underlying LID have remained elusive, three main risk factors for this condition have been conclusively identified in clinical studies. These are a young age of disease onset, disease severity (reflecting the extent of putaminal dopamine denervation) and high doses of L-DOPA.9,10
The latter two
factors are readily reproduced in both non-human primates and rodents by the administration of neurotoxins, which ablate the nigrostriatal pathway, followed by daily treatment with L-DOPA at a sufficient dosage.11–16
movements of hyperkinetic and/or dystonic phenotypes during the treatment period. These movements will gradually replace normal motor behaviour15
and overshadow the beneficial effect of L-DOPA.
Not all patients with PD develop dyskinesia and, similarly, a proportion of animals do not develop abnormal involuntary movements after chronic L-DOPA treatment. Thus, the animal models provide a valuable tool whereby molecular and neurochemical changes can be specifically correlated with dyskinesia rather than to
© TOUCH BRIEFINGS 2010
The animals develop abnormal involuntary
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