Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

Highlights

• Dyskinesia represents a debilitating complication of levodopa therapy for Parkinson's disease.

• There appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system circuitry.

• To propose a pathophysiological framework was timely and necessary.

• This review thus provides an overview of our current understanding of dyskinesia.

Abstract

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

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.