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

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

Toxin-Based Rodent Models of Parkinson’s Disease

A major pathological hallmark of Parkinson’s disease (PD) is a severe degeneration of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNc) projecting to the motor part of the striatum. Therefore, there is a long-standing interest in using animal models with severe nigrostriatal degeneration for experimental research. Pathophysiological and behavioral features of PD are best studied in mammalian species endowed with well-developed corticobasal ganglia thalamocortical loops, such as rodents. Different toxins can be used to generate nigrostriatal damage, including 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, and rotenone. Models based on 6-OHDA lesions provide the main advantage of a severe and reproducible DA lesions. Models based on MPTP provide easy and versatile tools to rapidly evaluate potential neuroprotective treatments. Models based on paraquat and rotenone are appealing for their relevance to some well-known environmental risk factors of the human PD, although they yield only partial dopaminergic degeneration and entail a considerable risk of nonspecific toxicity. The main general limitation of neurotoxin-based models is that they do not replicate some characterizing features of PD pathology, such as the formation of Lewy body–like proteinaceous aggregates or the anatomical pattern of neurodegeneration, which also affects nondopaminergic brain regions

Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with l-dopa–induced dyskinesia

l-dopa–induced dyskinesia (LID) is a common debilitating complication of dopamine replacement therapy in Parkinson's disease. Recent evidence suggests that LID may be linked causally to a hyperactivation of the Ras–ERK signaling cascade in the basal ganglia. We set out to determine whether specific targeting of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a brain-specific activator of the Ras–ERK pathway, may provide a therapy for LID. On the rodent abnormal involuntary movements scale, Ras-GRF1–deficient mice were significantly resistant to the development of dyskinesia during chronic l-dopa treatment. Furthermore, in a nonhuman primate model of LID, lentiviral vectors expressing dominant negative forms of Ras-GRF1 caused a dramatic reversion of dyskinesia severity leaving intact the therapeutic effect of l-dopa. These data reveal the central role of Ras-GRF1 in governing striatal adaptations to dopamine replacement therapy and validate a viable treatment for LID based on intracellular signaling modulation