The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism

Authors

• Sean L. Hammond, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Katriana A. Popichak, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Xi Li, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Lindsay G. Hunt, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Evan H. Richman, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Pranav U. Damale, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Edwin K. Chong, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Donald S. Backos, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Stephen Safe, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.).
• Ronald B. Tjalkens, Department of Environmental and Radiological Health Sciences (S.L.H., K.A.P., L.G.H., E.H.R., R.B.T.) and Department of Electrical and Computer Engineering (P.D., E.C.), Colorado State University, Fort Collins, Colorado; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (X.L., S.S.); and Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado (D.S.B.) ron.tjalkens@colostate.edu.

Document Type

Article

Abstract

The orphan nuclear receptor Nurr1 (also called nuclear receptor-4A2) regulates inflammatory gene expression in glial cells, as well as genes associated with homeostatic and trophic function in dopaminergic neurons. Despite these known functions of Nurr1, an endogenous ligand has not been discovered. We postulated that the activation of Nurr1 would suppress the activation of glia and thereby protect against loss of dopamine (DA) neurons after subacute lesioning with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our previous studies have shown that a synthetic Nurr1 ligand, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12), suppresses inflammatory gene expression in primary astrocytes and induces a dopaminergic phenotype in neurons. Pharmacokinetic analysis of C-DIM12 in mice by liquid chromatography-mass spectrometry demonstrated that approximately three times more compound concentrated in the brain than in plasma. Mice treated with four doses of MPTP + probenecid over 14 days were monitored for neurobehavioral function, loss of dopaminergic neurons, and glial activation. C-DIM12 protected against the loss of DA neurons in the substantia nigra pars compacta and DA terminals in the striatum, maintained a ramified phenotype in microglia, and suppressed activation of astrocytes. In vitro reporter assays demonstrated that C-DIM12 was an effective activator of Nurr1 transcription in neuronal cell lines. Computational modeling of C-DIM12 binding to the three-dimensional structure of human Nurr1 identified a high-affinity binding interaction with Nurr1 at the coactivator domain. Taken together, these data suggest that C-DIM12 is an activator of Nurr1 that suppresses glial activation and neuronal loss in vivo after treatment with MPTP, and that this receptor could be an efficacious target for disease modification in individuals with Parkinson's disease and related disorders.

Medical Subject Headings

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology); Active Transport, Cell Nucleus (drug effects); Animals; Brain (drug effects, metabolism, pathology); Cell Count; Cell Nucleus (drug effects, metabolism); Dopaminergic Neurons (drug effects, metabolism, pathology); Gene Expression Regulation (drug effects); Indoles (metabolism, pharmacokinetics, pharmacology, therapeutic use); Ligands; Male; Mice; Mice, Inbred C57BL; NF-kappa B (metabolism); Neuroglia (drug effects, pathology); Neuroprotective Agents (metabolism, pharmacokinetics, pharmacology, therapeutic use); Nuclear Receptor Subfamily 4, Group A, Member 2 (metabolism); Parkinsonian Disorders (chemically induced, drug therapy, metabolism, pathology); Phenotype; Signal Transduction (drug effects); Tissue Distribution

Publication Date

6-1-2018

Publication Title

The Journal of pharmacology and experimental therapeutics

E-ISSN

1521-0103

Volume

365

Issue

3

First Page

636

Last Page

651

PubMed ID

29626009

Digital Object Identifier (DOI)

10.1124/jpet.117.246389

Recommended Citation

Hammond, Sean L.; Popichak, Katriana A.; Li, Xi; Hunt, Lindsay G.; Richman, Evan H.; Damale, Pranav U.; Chong, Edwin K.; Backos, Donald S.; Safe, Stephen; and Tjalkens, Ronald B., "The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism" (2018). Translational Neuroscience. 2606.
https://scholar.barrowneuro.org/neurobiology/2606