Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease
Introduction
Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting approximately 1% of the population over 65, the mean age at which the disease is first diagnosed. PD was first described by James Parkinson (Parkinson, 1817, Parkinson, 2002) and consists of a syndrome including bradykinesia/akinesia, rigidity, postural abnormalities and tremor. The principal pathological characteristic of PD is the progressive death of the pigmented neurons of the Substantia Nigra pars compacta (SNc) (Hassler, 1938). The discovery, in 1960, that degeneration of the dopamine (DA) supplying neurons of the SNc causes parkinsonism (Ehringer and Hornykiewicz, 1960) opened the way for the development of pharmacological therapies for PD that act to enhance synaptic DA transmission using the DA precursor L-3,4-dihydroxypheylalanine (L-dopa) (Birkmayer and Hornykiewicz, 1961, Birkmayer and Hornykiewicz, 1962, Lees, 1994, Yahr et al., 1968).
The initial enthusiasm surrounding the positive effects of L-dopa in PD soon gave way to the recognition that long-term L-dopa therapy is complicated by the development of adverse events related to fluctuations in motor response. Motor fluctuations include ON–OFF fluctuations, sudden and unpredictable changes in mobility, and the wearing-off phenomenon, a decrease in the duration of L-dopa action (Quinn, 1998). However, the most debilitating class of motor fluctuation is involuntary movements known as L-dopa-induced dyskinesia (LID). These abnormal involuntary movements (AIMs) have been noted from the first introduction of L-dopa in the late 1960s (e.g. after 6 months of treatment over half of patients had developed dyskinesia) (Duvoisin, 1974). Long term experience has continued to report that the majority of L-dopa-treated patients experience dyskinesia, with up to 80% of patients having LID within 5 years of treatment (DeJong et al., 1987, Lees and Stern, 1983, Lesser et al., 1979, Marsden et al., 1982, Rajput et al., 1984). Eighty to ninety per cent of PD patients suffer from LID after 10 years of DA replacement therapy (Ahlskog and Muenter, 2001, Hauser et al., 2007), a condition affecting their quality of life (Hechtner et al., 2014). It should be noted that treatment-related dyskinesia are not solely a problem of L-dopa but DA receptor agonists are also capable of eliciting dyskinesia. Therefore, within this review, the term LID will be used to describe dopaminergic (DAergic) treatment-related dyskinesia generally. In the past 20 years, the understanding of the neural mechanisms underlying LID in PD has strongly advanced (Bezard et al., 2001a, Cenci et al., 1998, Fasano et al., 2010, Fieblinger et al., 2014b, Fisone and Bezard, 2011, Jenner, 2008, Picconi et al., 2003). Dyskinesia has been associated with a sequence of events that include pulsatile stimulation of DA receptors, downstream changes in proteins and genes, abnormalities in non-DAergic transmitter systems all of which combine to produce alterations in the neuronal firing patterns that signal between the basal ganglia and the cortex.
In this review, we aim at focusing on the changes affecting both DAergic and non-DAergic transmission, and particularly focus on changes observed at the peak-dose of L-dopa plasma concentrations, that is when dyskinesia are more commonly expressed, so called – ON dyskinesia, as opposed to OFF dyskinesia where the pathophysiology relates to low levels of DA. We also review other L-dopa-induced side-effects and highlight their pathophysiology as well as possible links to pathophysiology of LID. This overview has the goal to advance our understanding of LID, which might contribute to the development of novel therapeutic strategies aimed at preventing dyskinetic symptoms.
Section snippets
Clinical presentation
LID can be classified into peak-dose dyskinesia (involuntary movements that coincide with the peak-action of levodopa and thus period of best anti-parkinsonian action), diphasic dyskinesia (involuntary movements that emerge just before the DA replacement therapy turns the patient ON and that reappear at the end of the therapeutic benefit) and OFF period dystonia. The movement disorders most commonly associated with peak-dose LID are chorea, dystonia and ballism.
Chorea is characterized by
Animal models of LID and other L-dopa-induced abnormal behaviours
Understanding the pathophysiology of LID as a basis for therapeutic solutions has fuelled the search for valid, translational experimental models of the L-dopa-induced side effects in animals.
Pathophysiology of peak of dose LID
In the present review, we aimed at focusing on changes observed at the peak-dose of L-dopa plasma concentrations. Indeed, in the literature, LID pathophysiology refers to various states. In several papers, animals chronically exposed to L-dopa were considered as “dyskinetic” even when they were actually terminated OFF L-dopa (i.e. more than 3 h after their last L-dopa injection). While the OFF state is very interesting and informative on the neuronal plasticity induced by chronic treatment, it
Continuous delivery of L-dopa
The fluctuations in DA levels being key in generating LID, a number of attempts have been made for either improving L-dopa delivery (and hence pharmacokinetics), preventing DA catabolism, or producing long-lasting DA agonists. This latter proposal could be achieved either by developing DA agonists with long half-life or by a galenic improvement leading to slow release formulations. The long-standing continuous-versus-intermittent-receptor-stimulation discussion has led to such attempts with
Concluding remarks
The present review describes the unprecedented accumulation of knowledge on the pathophysiology of LID in particular and of L-dopa-induced disorders in general. One cannot however fail to notice the discrepancy between such knowledge and the yet limited therapeutic armoury. We are indeed basically left with amantadine or DBS to manage the severity of dyskinesia and we have no real option for delaying, or even better prevent the appearance of these troublesome side-effects.
What are the main
Acknowledgements
This review was supported by the Fondation de France and Grant LABEX BRAIN ANR-10-LABX-43. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Although extensive, this review cannot be exhaustive. We therefore apologize the many authors whose work has not be quoted.
Glossary
- 5-HT
- serotonin
- 5-HT
- 5-hydroxytryptamine
- 6FD
- 6-[18F]fluoro-L-dopa
- 6-OHDA
- 6-hydroxydopamine
- AADC
- L-amino acid decarboxylase
- AADCI
- AADC peripheral inhibitors
- AC5
- adenylyl cyclase type 5
- ACh
- acetylcholine
- AIMs
- abnormal involuntary movements
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- AP-1
- activator protein 1
- BDNF
- brain derived neurotrophic factor
- BST
- bed nucleus of the stria terminalis
- CaMKII
- Ca2+/calmodulin-dependent protein kinase II
- cAMP
- cyclic adenosine monophosphate
- CBF
- cerebral blood flow
- CDRS
- Clinical
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