Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription.
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.
Yang
Lichuan
L
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA.
Calingasan
Noel Y
NY
Thomas
Bobby
B
Chaturvedi
Rajnish K
RK
Kiaei
Mahmoud
M
Wille
Elizabeth J
EJ
Liby
Karen T
KT
Williams
Charlotte
C
Royce
Darlene
D
Risingsong
Renee
R
Musiek
Eric S
ES
Morrow
Jason D
JD
Sporn
Michael
M
Beal
M Flint
MF
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
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