title: Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription.
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, 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.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.forename: Rajnish K
authors.initials: RK
authors.lastname: Chaturvedi
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Wille
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.forename: Charlotte
authors.initials: C
authors.lastname: Williams
authors.forename: Darlene
authors.initials: D
authors.lastname: Royce
authors.forename: Renee
authors.initials: R
authors.lastname: Risingsong
authors.forename: Eric S
authors.initials: ES
authors.lastname: Musiek
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Michael
authors.initials: M
authors.lastname: Sporn
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000473:pathology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013729:Terpenes / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C530803:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl amide; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013729:Terpenes; D009828:Oleanolic Acid