Journal Article

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

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

2009

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Alzheimer's disease / Alzheimers disease / Analysis / Animals / Antifungal agents / Antioxidants / Antioxidants (Nutrients) / Antioxidants - metabolism / Cell Line, Tumor / Chemical compounds / Chromatography / Cytosol / Damage accumulation / Deoxyguanosine / Deoxyribonucleic acid / Detoxification / DNA / DNA polymerase / Dopamine / Dopamine receptors / Embryo fibroblasts / Embryos / Enzymes / Fibroblasts / Gene expression / Genes / Glutathione / Homeostasis / Hospitals / Humans / Huntington's disease / Isoprostanes / Lesions / Male / Malondialdehyde / Medical schools / Medical treatment / Mice / Mice, Inbred C57BL / Models, Biological / Movement disorders / MPTP / Neostriatum / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - pathology / Neurological diseases / Neurological Disorders / Neurological Disorders/Alzheimer Disease / Neurological Disorders/Movement Disorders / Neurological Disorders/Neuropharmacology / Neurology / Neuroprotection / Neuroscience / Neuroscience/Motor Systems / Neurosciences / Neurotoxicity / Neurotoxins / NF-E2-Related Factor 2 - metabolism / Nitrotyrosine / Nuclei (cytology) / Oleanolic Acid - analogs & derivatives / Oleanolic Acid - pharmacokinetics / Oleanolic Acid - pharmacology / Oral administration / Oxygen / Parkinson's disease / Pharmacology / Polymerase chain reaction / Proteins / Rats / Rats, Inbred Lew / Reactive oxygen species / Rodents / Signal transduction / Signaling / Synuclein / Terpenes - metabolism / Thermus aquaticus / Transcription (Genetics) / Transcription, Genetic / Translocation