Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis

• Published in: Free radical biology & medicine Vol. 51; no. 1; pp. 88 - 96
• Main Authors: Neymotin, Arie, Calingasan, Noel Y., Wille, Elizabeth, Naseri, Nima, Petri, Susanne, Damiano, Maria, Liby, Karen T., Risingsong, Renee, Sporn, Michael, Beal, M. Flint, Kiaei, Mahmoud
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2011
• Subjects: Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - metabolism; Animal models; Animals; Antioxidants; Cell culture; Cell Line; Cell Nucleus - enzymology; disease course; Disease Models, Animal; Free radicals; G93A; gene expression regulation; Inflammation; Inflammation - metabolism; Major Histocompatibility Complex - genetics; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Motor neuron degeneration; Motor task performance; mutants; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neuroprotection; neuroprotective effect; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nuclear transport; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - metabolism; Oleanolic Acid - pharmacology; Oleanolic Acid - therapeutic use; Oxidative damage; Oxidative Stress; pathogenesis; proteins; Proteins - genetics; Proteins - metabolism; Regulatory sequences; RNA, Messenger - biosynthesis; sclerosis; Signal Transduction; SOD1; Superoxide dismutase; Superoxide Dismutase - biosynthesis; Superoxide Dismutase - genetics; Survival; Triterpenoids; weight loss; Western blotting; G93A; Free radicals; Triterpenoids; Oxidative damage; Inflammation; Motor neuron degeneration; SOD1
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2011.03.027

Oxidative damage, neuroinflammation, and mitochondrial dysfunction contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), and these pathologic processes are tightly regulated by the Nrf2/ARE (NF-E2-related factor 2/antioxidant response element) signaling program. Therefore, modulation of the Nrf2/ARE pathway is an attractive therapeutic target for neurodegenerative diseases such as ALS. We examined two triterpenoids, CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) ethylamide and CDDO trifluoroethylamide (CDDO-TFEA), that potently activate Nrf2/ARE in a cell culture model of ALS and in the G93A SOD1 mouse model of ALS. Treatment of NSC-34 cells stably expressing mutant G93A SOD1 with CDDO-TFEA upregulated Nrf2 expression and resulted in translocation of Nrf2 into the nucleus. Western blot analysis showed an increase in the expression of Nrf2/ARE-regulated proteins. When treatment started at a “presymptomatic age” of 30days, both of these compounds significantly attenuated weight loss, enhanced motor performance, and extended the survival of G93A SOD1 mice. Treatment started at a “symptomatic age,” as assessed by impaired motor performance, was neuroprotective and slowed disease progression. These findings provide further evidence that compounds that activate the Nrf2/ARE signaling pathway may be useful in the treatment of ALS.