Neuroprotective Effects of the Triterpenoid, CDDO Methyl Amide, a Potent Inducer of Nrf2-mediated Transcription

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2009 Jun 2

PMID 19484125

Citations 83

Authors

Lichuan Yang

Noel Y Calingasan

Bobby Thomas

Rajnish K Chaturvedi

Mahmoud Kiaei

Elizabeth J Wille

Karen T Liby

Charlotte Williams

Darlene Royce

Renee Risingsong

Eric S Musiek

Jason D Morrow

Michael Sporn

M Flint Beal

Affiliations

Soon will be listed here.

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.

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References

Montine T, Beal M, Robertson D, Cudkowicz M, Biaggioni I, ODonnell H . Cerebrospinal fluid F2-isoprostanes are elevated in Huntington's disease. Neurology. 1999; 52(5):1104-5. DOI: 10.1212/wnl.52.5.1104. View

Klivenyi P, Siwek D, Gardian G, Yang L, Starkov A, Cleren C . Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol Dis. 2005; 21(3):541-8. DOI: 10.1016/j.nbd.2005.08.018. View

Hofer T, Seo A, Prudencio M, Leeuwenburgh C . A method to determine RNA and DNA oxidation simultaneously by HPLC-ECD: greater RNA than DNA oxidation in rat liver after doxorubicin administration. Biol Chem. 2006; 387(1):103-11. DOI: 10.1515/BC.2006.014. View

Klivenyi P, Andreassen O, Ferrante R, Dedeoglu A, Mueller G, Lancelot E . Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. J Neurosci. 2000; 20(1):1-7. PMC: 6774090. View

Yang L, Calingasan N, Chen J, Ley J, Becker D, Beal M . A novel azulenyl nitrone antioxidant protects against MPTP and 3-nitropropionic acid neurotoxicities. Exp Neurol. 2004; 191(1):86-93. DOI: 10.1016/j.expneurol.2004.07.012. View

Trinh K, Moore K, Wes P, Muchowski P, Dey J, Andrews L . Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson's disease. J Neurosci. 2008; 28(2):465-72. PMC: 6670551. DOI: 10.1523/JNEUROSCI.4778-07.2008. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Holland P, Abramson R, Watson R, Gelfand D . Detection of specific polymerase chain reaction product by utilizing the 5'----3' exonuclease activity of Thermus aquaticus DNA polymerase. Proc Natl Acad Sci U S A. 1991; 88(16):7276-80. PMC: 52277. DOI: 10.1073/pnas.88.16.7276. View

Norris E, Uryu K, Leight S, Giasson B, Trojanowski J, Lee V . Pesticide exposure exacerbates alpha-synucleinopathy in an A53T transgenic mouse model. Am J Pathol. 2007; 170(2):658-66. PMC: 1851868. DOI: 10.2353/ajpath.2007.060359. View

10.

Honda T, Honda Y, Favaloro Jr F, Gribble G, Suh N, Place A . A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production. Bioorg Med Chem Lett. 2002; 12(7):1027-30. DOI: 10.1016/s0960-894x(02)00105-1. View

11.

Holtzclaw W, Dinkova-Kostova A, Talalay P . Protection against electrophile and oxidative stress by induction of phase 2 genes: the quest for the elusive sensor that responds to inducers. Adv Enzyme Regul. 2004; 44:335-67. DOI: 10.1016/j.advenzreg.2003.11.013. View

12.

Martin L, Liu Z, Chen K, Price A, Pan Y, Swaby J . Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J Comp Neurol. 2006; 500(1):20-46. DOI: 10.1002/cne.21160. View

13.

Martin L, Pan Y, Price A, Sterling W, Copeland N, Jenkins N . Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci. 2006; 26(1):41-50. PMC: 6381830. DOI: 10.1523/JNEUROSCI.4308-05.2006. View

14.

Liu G, Eggler A, Dietz B, Mesecar A, Bolton J, Pezzuto J . Screening method for the discovery of potential cancer chemoprevention agents based on mass spectrometric detection of alkylated Keap1. Anal Chem. 2005; 77(19):6407-14. DOI: 10.1021/ac050892r. View

15.

Leung L, Kwong M, Hou S, Lee C, Chan J . Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem. 2003; 278(48):48021-9. DOI: 10.1074/jbc.M308439200. View

16.

Wyss-Coray T . Inflammation in Alzheimer disease: driving force, bystander or beneficial response?. Nat Med. 2006; 12(9):1005-15. DOI: 10.1038/nm1484. View

17.

Yates M, Kwak M, Egner P, Groopman J, Bodreddigari S, Sutter T . Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res. 2006; 66(4):2488-94. DOI: 10.1158/0008-5472.CAN-05-3823. View

18.

Manning-Bog A, McCormack A, Li J, Uversky V, Fink A, Di Monte D . The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem. 2001; 277(3):1641-4. DOI: 10.1074/jbc.C100560200. View

19.

Calkins M, Jakel R, Johnson D, Chan K, Kan Y, Johnson J . Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci U S A. 2004; 102(1):244-9. PMC: 538748. DOI: 10.1073/pnas.0408487101. View

20.

Lee J, Li J, Johnson D, Stein T, Kraft A, Calkins M . Nrf2, a multi-organ protector?. FASEB J. 2005; 19(9):1061-6. DOI: 10.1096/fj.04-2591hyp. View