Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription

PLoS One. 2009 Jun 1;4(6):e5757. doi: 10.1371/journal.pone.0005757.


The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes. CDDO-MA blocked t-butylhydroperoxide-induced production of reactive oxygen species (ROS) by activation of ARE genes only in wild type, but not Nrf2 knockout mouse embryonic fibroblasts. Oral administration of CDDO-MA resulted in significant protection against MPTP-induced nigrostriatal dopaminergic neurodegeneration, pathological alpha-synuclein accumulation and oxidative damage in mice. Additionally, CDDO-MA treatment in rats produced significant rescue against striatal lesions caused by the neurotoxin 3-NP, and associated increases in the oxidative damage markers malondialdehyde, F(2)-Isoprostanes, 8-hydroxy-2-deoxyguanosine, 3-nitrotyrosine, and impaired glutathione homeostasis. Our results indicate that the CDDO-MA renders its neuroprotective effects through its potent activation of the Nrf2/ARE pathway, and suggest that triterpenoids may be beneficial for the treatment of neurodegenerative diseases like Parkinson's disease and Huntington's disease.

Publication types

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

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Cell Line, Tumor
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • NF-E2-Related Factor 2 / metabolism*
  • Neurodegenerative Diseases / pathology
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacokinetics
  • Oleanolic Acid / pharmacology
  • Rats
  • Rats, Inbred Lew
  • Terpenes / metabolism
  • Transcription, Genetic*


  • 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl amide
  • Antioxidants
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Terpenes
  • Oleanolic Acid