Levodopa-induced dyskinesia (LID) is a frequent complication of long-term treatment with L-DOPA in Parkinson's disease (PD) patients. Choreothetosic movements of LID are extremely disabling and limit significantly functionality and quality of life of advanced PD patients. Treatment of LID is rather unsatisfactory, being limited in the majority of cases to reduction of dopaminergic therapy, in turn causing worsening of parkinsonism.
The pathophysiology of LID in PD is rather complex. Preclinical and clinical studies point on excessive glutamate activity at level of cortical-subcortical frontostriatal motor circuitries. Excessive glutamate transmission may also contribute to neurotoxicity in PD. In the present study we will investigate the relationships between mGlu3 and mGlu5 receptor polymorphisms and LID in a large PD cohort (>1500 subjects). This will be coupled with preclinical investigations on the role of mGlu3 and mGlu5 receptors in neurotoxicity and LID in experimental models of PD (6-OHDA lesion in rats and MPTP lesion in mice).
This project will combine robust preclinical studies with up-to-date genomics investigation in PD patients. The results, therefore, will provide a complete scenario on the role of mGlu-mediated transmission in LID in PD, and improve current knowledge on the pathogenesis and treatment of LID in PD as well as on the feasibility of identifying by genomics assay subjects at risk of developing LID. These findings may prove useful for future strategies of prevention and treatment of LID, a currently unmet need for treatment of PD. In addition, the project will establish whether a drug that inhibits mGlu5 receptors and a drug that activates mGlu3 receptors act synergistically in protecting nigro-striatal neurons in a model of progressive degeneration occurring in PD. The identification of effective neuroprotective strategies is a further unmet need in the treatment of PD with potentially high impact for human societies.
LID is a common complication of chronic treatment with L-DOPA in PD, with significant negative impact on daily functioning and quality of life. Treatment of LID is rather inconclusive at present, being limited in the majority of cases to reduction of daily doses of DRT. Amantadine, an antiparkinsonian drug with glutamate antagonist activity, is the only available treatment with discrete antidyskinetic activity, but it is frequently associated with cardiovascular and neuropsychiatric adverse effects.
As discussed above, a number of preclinical studies suggest a key role for glutamatergic transmission in the development of LID. In particular, mGlu receptors are a promising target for the treatment of LID in PD. This project, combining genomics studies and preclinical studies in rodents may shed new lights. The project aims at investigating new approaches in the treatment of motor complications associated with L-DOPA treatment in PD. The expected results may pave the way to the development of a combined treatment of drugs interacting with mGlu5 and mGlu3 receptors in the management of PD patients affected by LID.
This project combines robust preclinical approach to the study of the role of metabotropic glutamatatergic transmission on LID with the innovative search for characterization of the relationship between polymorphisms of mGlu3 and mGlu5 receptors and LID in PD patients.
The preclinical study will contribute at defining the interactions between mGlu3 and mGlu5 receptors in rodent models of LID. In addition, the project will establish whether a drug that inhibits mGlu5 receptors and a drug that activates mGlu3 receptors act synergistic in protecting nigro-striatal neurons in a model that recapitulates the progressive degeneration occurring in PD. The identification of effective neuroprotective strategies is an unmet need in the treatment of PD
The clinical study will clarify the relationships between polymorphisms of mGlu3 and mGlu5 receptors and the development and severity of LID is a large cohort of PD patients. The strength of this project lies in the identification of PD patients predisposed to develop LID. To this end, we will rely on the use of the advanced technology, iPLEX Gold Mass Array Sequenom. This method is based on the amplification of DNA regions of interest, the subsequent extension by specific primers and determination of the genotype by mass spectroscopy. iPLEX allows to analyze up to 30 different polymorphisms for each DNA sample and more than 300 samples of DNA simultaneously.
The availability of a complete database of demographic, clinical and therapeutic features of more than 1500 PD patients will allow rigorous analysis of the possible correlations. If positive, the results will provide the basis for future identification of subjects at risk of developing LID. This will contribute to tailoring pharmacological therapy of PD patients with the aim of reducing a severe complication of the late disease stage.