Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Selective brain penetrable Nurr1 transactivator for treating Parkinson’s disease

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

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Oncotarget. 2016; 7:7469-7479. https://doi.org/10.18632/oncotarget.7191

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Abstract

Jun Wang1,2, Weina Bi1, Wei Zhao1, Merina Varghese1, Rick J. Koch3, Ruth H. Walker3, Roshantha A. Chandraratna4, Martin E. Sanders4, Amanda Janesick5, Bruce Blumberg5, Libby Ward1, Lap Ho1 and Giulio M. Pasinetti1,2

1 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

2 Geriatric Research, Education and Clinical Center, Bronx, NY, USA

3 Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA

4 Io Therapeutics Inc., Santa Ana, CA, USA

5 Departments of Developmental and Cell Biology, and Pharmaceutical Sciences, University of California, Irvine, CA, USA

Correspondence to:

Giulio M. Pasinetti, email:

Keywords: brain bioavailable, dopaminergic, nuclear receptor related-1 protein, Parkinson’s disease, retinoid X receptor, Gerotarget

Received: September 23, 2015 Accepted: January 23, 2016 Published: February 04, 2016

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.


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