ArticleToxicological sciences : an official journal of the Society of Toxicology2015
Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's disease.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 51 citations in OpenAlex.
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- Peripheral mast cells derive the effects of acupuncture in Parkinson's disease.Frontiers in aging neuroscience · 2024Article
- A novel NR4A2-HuR axis promotes pancreatic cancer growth and tumorigenesis that is inhibited by NR4A2 antagonists.American journal of cancer research · 2024Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- A Nurr1 ligand C-DIM12 attenuates brain inflammation and improves functional recovery after intracerebral hemorrhage in mice.Scientific reports · 2022Article
- Orphan nuclear receptor 4A1 (NR4A1) and novel ligands.Essays in biochemistry · 2021Article
- Astrocyte inflammatory signaling mediates α-synuclein aggregation and dopaminergic neuronal loss following viral encephalitis.Experimental neurology · 2021Article
- Nuclear receptors of NR1 and NR4 subfamilies in the regulation of microglial functions and pathology.Pharmacology research & perspectives · 2021Review
- Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1.ACS chemical biology · 2021Article
- The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer.Molecular cancer research : MCR · 2021Review
- A Low-Cost, Autonomous Gait Detection and Estimation System for Analyzing Gait Impairments in Mice.Journal of healthcare engineering · 2021Article
- Nuclear receptor 4A2 (NR4A2) is a druggable target for glioblastomas.Journal of neuro-oncology · 2020Article
- Structure-dependent activation of gene expression by bis-indole and quinoline-derived activators of nuclear receptor 4A2.Chemical biology & drug design · 2019Review
- Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death.Molecular neurobiology · 2019Review
- The neuroprotective action of 3,3'-diindolylmethane against ischemia involves an inhibition of apoptosis and autophagy that depends on HDAC and AhR/CYP1A1 but not ERα/CYP19A1 signaling.Apoptosis : an international journal on programmed cell death · 2019Article
- Nurr1 Promotes Lung Cancer Apoptosis Via Enhancing Mitochondrial Stress and p53-Drp1 Pathway.Open life sciences · 2019Article
- Compensatory Expression of Nur77 and Nurr1 Regulates NF-Molecular pharmacology · 2018Article
- The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(The Journal of pharmacology and experimental therapeutics · 2018Article
- Steroid and Xenobiotic Receptor Signalling in Apoptosis and Autophagy of the Nervous System.International journal of molecular sciences · 2017Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The orphan nuclear receptor NR4A2 (Nurr1) constitutively regulates inflammatory gene expression in glial cells by suppressing DNA binding activity of NF-κB. We recently reported that novel 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compounds that activate NR4A family nuclear receptors in cancer lines also suppress inflammatory gene expression in primary astrocytes and prevent loss of dopaminergic neurons in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp). In this study, we postulated that the basis for this neuroprotection involves blockade of glial activation and subsequent expression of NF-κB-regulated inflammatory genes. To examine this mechanism, we treated transgenic NF-κB/EGFP reporter mice with MPTPp for 7 days (MPTPp7d) followed by daily oral gavage with either vehicle (corn oil; MPTPp14d) or C-DIMs containing p-methoxyphenyl (C-DIM5), p-hydroxyphenyl (C-DIM8), or p-chlorophenyl (C-DIM12) groups. Each compound conferred significant protection against progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), even when given after 7 days of dosing with MPTPp. C-DIM12 had the greatest neuroprotective activity in MPTPp-treated mice, and was also the most potent compound in suppressing activation of microglia and astrocytes, expression of cytokines and chemokines in quantitative polymerase chain reaction (qPCR) array studies, and in reducing expression of NF-κB/EGFP in the SN. C-DIM12 prevented nuclear export of Nurr1 in dopaminergic neurons and enhanced expression of the Nurr1-regulated proteins tyrosine hydroxylase and the dopamine transporter. These data indicate that NR4A-active C-DIM compounds protect against loss of dopamine neurons in the MPTPp model of PD by preventing glial-mediated neuronal injury and by supporting a dopaminergic phenotype in TH-positive neurons in the SNpc.
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