title: Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's disease.
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.
authors.affiliation: *Department of Environmental and Radiological Health Sciences, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado 80523-1680, Texas A&M Health Science Center, Houston, TX 77030, Texas and Department of Veterinary Physiology and Pharmacology, Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University, College Station, TX 77843, Texas.
authors.forename: Briana R
authors.initials: BR
authors.lastname: De Miranda
authors.affiliation: *Department of Environmental and Radiological Health Sciences, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado 80523-1680, Texas A&M Health Science Center, Houston, TX 77030, Texas and Department of Veterinary Physiology and Pharmacology, Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University, College Station, TX 77843, Texas.
authors.forename: Katriana A
authors.initials: KA
authors.lastname: Popichak
authors.affiliation: *Department of Environmental and Radiological Health Sciences, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado 80523-1680, Texas A&M Health Science Center, Houston, TX 77030, Texas and Department of Veterinary Physiology and Pharmacology, Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University, College Station, TX 77843, Texas.
authors.forename: Sean L
authors.initials: SL
authors.lastname: Hammond
authors.affiliation: *Department of Environmental and Radiological Health Sciences, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado 80523-1680, Texas A&M Health Science Center, Houston, TX 77030, Texas and Department of Veterinary Physiology and Pharmacology, Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University, College Station, TX 77843, Texas.
authors.forename: James A
authors.initials: JA
authors.lastname: Miller
authors.affiliation: *Department of Environmental and Radiological Health Sciences, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado 80523-1680, Texas A&M Health Science Center, Houston, TX 77030, Texas and Department of Veterinary Physiology and Pharmacology, Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University, College Station, TX 77843, Texas *Department of Environmental and Radiological Health Sciences, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado 80523-1680, Texas A&M Health Science Center, Houston, TX 77030, Texas and Department of Veterinary Physiology and Pharmacology, Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University, College Station, TX 77843, Texas.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: *Department of Environmental and Radiological Health Sciences, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado 80523-1680, Texas A&M Health Science Center, Houston, TX 77030, Texas and Department of Veterinary Physiology and Pharmacology, Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University, College Station, TX 77843, Texas Ron.Tjalkens@colostate.edu.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Tjalkens
mesh_terms: D000818:Animals; D000840:Anisoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C534880:1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane; C552530:1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane; C545255:1,1-bis(3'-indolyl)-1-(p-anisyl)methane; D000840:Anisoles; D000978:Antiparkinson Agents; D007211:Indoles; D016328:NF-kappa B; D010636:Phenols; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: Parkinson’s disease; microglia; neuroinflammation; orphan nuclear receptors