title: Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease.
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.
authors: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Geriatric Research, Education and Clinical Center, Bronx, NY, USA.
authors: Jun
authors: J
authors: Wang
authors: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Weina
authors: W
authors: Bi
authors: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Wei
authors: W
authors: Zhao
authors: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Merina
authors: M
authors: Varghese
authors: Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
authors: Rick J
authors: RJ
authors: Koch
authors: Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
authors: Ruth H
authors: RH
authors: Walker
authors: Io Therapeutics Inc., Santa Ana, CA, USA.
authors: Roshantha A
authors: RA
authors: Chandraratna
authors: Io Therapeutics Inc., Santa Ana, CA, USA.
authors: Martin E
authors: ME
authors: Sanders
authors: Departments of Developmental and Cell Biology, and Pharmaceutical Sciences, University of California, Irvine, CA, USA.
authors: Amanda
authors: A
authors: Janesick
authors: Departments of Developmental and Cell Biology, and Pharmaceutical Sciences, University of California, Irvine, CA, USA.
authors: Bruce
authors: B
authors: Blumberg
authors: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Libby
authors: L
authors: Ward
authors: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Lap
authors: L
authors: Ho
authors: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Geriatric Research, Education and Clinical Center, Bronx, NY, USA.
authors: Giulio M
authors: GM
authors: Pasinetti
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D000066829:Neuroprotection / Q000187:drug effects; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000819:agonists*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D015534:Trans-Activators / Q000494:pharmacology*
chemical_list: D003521:Cyclopropanes; C000613032:IRX4204; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D015534:Trans-Activators
keywords: Gerotarget; Parkinson’s disease; brain bioavailable; dopaminergic; nuclear receptor related-1 protein; retinoid X receptor