Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's disease

Toxicol Sci. 2015 Feb;143(2):360-73. doi: 10.1093/toxsci/kfu236. Epub 2014 Nov 17.


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.

Keywords: Parkinson’s disease; microglia; neuroinflammation; orphan nuclear receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anisoles / chemistry
  • Anisoles / pharmacology*
  • Anisoles / therapeutic use
  • Antiparkinson Agents / chemistry
  • Antiparkinson Agents / pharmacology*
  • Antiparkinson Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Cell Count
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / pathology
  • Green Fluorescent Proteins / genetics
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • MPTP Poisoning / metabolism
  • MPTP Poisoning / pathology
  • MPTP Poisoning / prevention & control*
  • Mice, Transgenic
  • NF-kappa B / genetics
  • Neuroglia / drug effects*
  • Neuroglia / metabolism
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Parkinson Disease / prevention & control*
  • Phenols / chemistry
  • Phenols / pharmacology*
  • Phenols / therapeutic use


  • 1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane
  • 1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane
  • 1,1-bis(3'-indolyl)-1-(p-anisyl)methane
  • Anisoles
  • Antiparkinson Agents
  • Indoles
  • NF-kappa B
  • Phenols
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins