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

Lichuan Yang, Noel Y. Calingasan, Bobby Thomas, Rajnish K. Charturvedi, Mahmoud Kiaei, Elizabeth J. Wille, Karen T. Liby, Charlotte Williams, Darlene Royce, Renee Risingson, Eric S. Musiek, Jason D. Morrow, Michael Sporn, M. Flint Beal

Research output: Contribution to journalArticle

123 Scopus citations

Abstract

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, F2-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.

Original languageEnglish (US)
Article numbere5757
JournalPloS one
Volume4
Issue number6
DOIs
StatePublished - Jun 1 2009

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Yang, L., Calingasan, N. Y., Thomas, B., Charturvedi, R. K., Kiaei, M., Wille, E. J., Liby, K. T., Williams, C., Royce, D., Risingson, R., Musiek, E. S., Morrow, J. D., Sporn, M., & Beal, M. F. (2009). Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PloS one, 4(6), [e5757]. https://doi.org/10.1371/journal.pone.0005757