Jayakumar Rajadas
Stanford University, USA
Title: Novel pharmaceutical interventions to relieve L-DOPA induced dyskinesia in Parkinson’s disease
Biography
Biography: Jayakumar Rajadas
Abstract
Parkinson’s disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the basal ganglia. The golden standard for the treatment of PD is the dopamine (DA) replacement therapy with L-DOPA. DA acts on DA receptors which belong to the superfamily of G Protein coupled receptors (GPCRs). However chronic treatment with L-DOPA results in super sensitivity of DA receptors and unwanted side effects commonly known as L-DOPA induced dyskinesia. Here we screened different formulations of L-DOPA oral route delivery which could result in a slow, sustained and timely delivery of L-DOPA along with repurposed GPCR receptor antagonists that can up regulate two of the G protein coupled receptor kinases GRK3 and 6 in brain that are down regulated in experimental animal models of PD. Our in vitro data in striatal neuronal culture in the presence of DA and GPCR receptor antagonists showed an upregulation of GRK3 and 6 after 24 hours of treatment at lower doses of DA. The behavioral studies in unilateral PD mice with DOPA formulations showed oral delivery of DOPA relieved the akinesia seen in Parkinson’s disease and at the same time had less dyskinetic effects as revealed by mouse cylinder test and AIMS respectively. Together our behavioral and signaling data demonstrate that L-DOPA delivered orally in a sustained release form along with the peripheral DOPA decarboxylase inhibitors carbidopa and benserazide could relieve the dyskinetic effects due to L-DOPA therapy in Parkinson’s disease.