The overall goal of the proposed studies is to characterize the role of IRX4204, a second generation retinoid X receptor (RXR) agonist in activating nuclear receptor related-1 protein (Nurr1)-mediated neuroprotection and preventing ?-synuclein (?-syn) neurodegeneration. Specifically, we propose to conduct plasma pharmacokinetic and brain accumulation studies to establish drug dose, plasma concentration, brain concentration and Nurr1 downstream gene response relationship to better understand the efficacy, safety and mechanisms of action of IRX4204 for translational Parkinson's disease (PD) drug discovery. Moreover, as a proof of concept, we will test whether oral administration of IRX4204 can protect against ?-syn-mediated neurodegeneration in a rat model of PD.
Parkinson's disease (PD) is the second most common neurodegenerative disease of aging and has a major negative impact on the quality of life of veterans enrolled in the Veterans Administration Health Care System. Current therapies for PD are symptomatic treatments for motor symptoms and motor complications of the disease. To date, there are no disease modifying drug treatment which has conclusively shown to be neuroprotective or slow disease progression. Therefore, developing novel immediate therapeutic agents to prevent /slow PD progression is of fundamental importance. Our studies will provide scientific impetus for immediate translational application of IRX4204 as a novel intervention with disease modifying activity for the treatment of ?-syn-mediated neurodegenerative disorders, such as PD and dementia with Lewy bodies.
