Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease.

Jun Wang,Libby Ward,Merina Varghese,Wei Zhao,Weina Bi,Martin E Sanders,Giulio M Pasinetti,Lap Ho,Bruce Blumberg,Ruth H Walker,Roshantha A Chandraratna,Rick J Koch,Amanda Janesick

doi:10.18632/oncotarget.7191

Abstract

Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) andattenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease of aging, which currently affects approximately 1-2% of the world’s population over age 65
We found that IRX4204 can partially activate retinoid X receptor (RXR) at a concentration of 0.1 nM and fully activates all three RXRs (α, β and γ) at a concentration of 1 nM (Figure 1b)
We found that IRX4204 is thousand times more potent for RXR than retinoic acid receptors (RARα, β and γ, Figure 1b)

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease of aging, which currently affects approximately 1-2% of the world’s population over age 65. PD is associated with increased disability, lower quality of life, increased mortality, and increased healthcare costs across all stages of the disease. The motor symptoms of PD are believed to begin after 40-60% of the dopamine cells in the substantia nigra (SN) pars compacta are lost [6]. Progression of motor symptoms is related to dopamine cell loss and can be assessed clinically using the Unified Parkinson’s Disease Rating Scale part III (UPDRS-3), which is sensitive to treatment related changes. Motor symptoms produce significant disability, worsen quality of life, and advance even when treated optimally with currently available symptomatic therapies

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Conclusion