Dyskinesias are uncontrollable involuntary body movements that constitute a major clinical problem associated with the long term treatment of Parkinson’s disease (PD) using levodopa (L-DOPA), the most widely prescribed treatment for PD. This research project seeks to improve the clinical utility of L-DOPA by reducing the development of motor complications induced by L-DOPA through coadministration with a novel drug therapy that may also provide Symptoms & Side Effects relief of the disease.
Recently, a team of scientists from the Vanderbilt Program in Drug Discovery at Vanderbilt University Medical Center, funded through a MJFF LEAPS award, identified a series of compounds that activate a neurotransmitter receptor that may reduce activity of a brain pathway that is overactive in PD patients. This series of compounds, known as metabotropic glutamate receptor subtype 4 positive allosteric modulators (mGluR4 PAMs), produces robust antiparkinson-like effects in several pre-clinical models of PD. In the current research project, a collaboration between Lund University, Sweden, and Vanderbilt University, the effects of these mGluR4 PAMs will be evaluated when given in combination with L-DOPA on the induction of L-DOPA related dyskinesias in a well known pre-clinical model of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
PD is treated with medicines that replace the neurotransmitter dopamine that is lost in Parkinson’s patients, such as L-DOPA. These medicines have severe adverse effects and lose reliable efficacy as the disease progresses. This program endeavors to characterize a new treatment that could reduce the motor complications induced by L-DOPA while providing Symptoms & Side Effects relief of the disease. If successful, this could provide a major advance in treatment of PD.
If successful, this research project will provide critical information on a novel treatment approach for PD and the reduction of L-DOPA induced dyskinesias. In addition, these studies will provide valuable new information on the impact of regulation of transmission in an identified brain circuit impacted by PD on symptoms of the disease and its involvement in L-DOPA induced dyskinesias. Such findings could provide a major advance in stimulating other treatment strategies that are focused on altering activity in this brain circuit.
Metabotropic glutamate receptor type 4 (mGluR4) is abundantly expressed in certain neural circuits within the basal ganglia, and pharmacological activation of this receptor has been reported to stimulate movement in models of Parkinson’s disease (PD). In this project we have compared the therapeutic potential of a positive allosteric modulator (PAM) (VU0364770) and an orthosteric agonist of mGluR4 (LSP1-2111) using a model of PD and levodopa-induced dyskinesia. In tests of general motor dexterity or forelimb use, neither compound produced any significant improvement when given alone. VU0364770 could, however, potentiate the effect of very low doses of levodopa in increasing the models’ global motor activity. This property was not shared by LSP1-2111, which did not improve the effect of low levodopa doses. Neither compound modified the severity of established levodopa-induced dyskinesias when administered acutely to already dyskinetic models. When administered chronically together with levodopa, neither compound modified either the incidence or the time course of dyskinesias. Chronic treatment with these compounds alone did not induce any dyskinetic behavior. These results suggest that the potential utility of mGluR4 PAMs in the treatment of PD may depend on their capacity to potentiate the anti-akinetic efficacy of low levodopa doses. For this application, mGluR4 PAMs appear more effective than orthosteric agonists of mGluR4.
Presentations & Publications
Abstract at The 8th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience in Barcelona, Spain (July 2011). Iderberg H, Jones CK, Niswender CM, Conn PJ, Cenci MA. Positive allosteric modulation of mGluR4 potentiates the antiparkinsonian