title: Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis.
abstract: 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.
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA.
authors: Arie
authors: A
authors: Neymotin
authors: Noel Y
authors: NY
authors: Calingasan
authors: Elizabeth
authors: E
authors: Wille
authors: Nima
authors: N
authors: Naseri
authors: Susanne
authors: S
authors: Petri
authors: Maria
authors: M
authors: Damiano
authors: Karen T
authors: KT
authors: Liby
authors: Renee
authors: R
authors: Risingsong
authors: Michael
authors: M
authors: Sporn
authors: M Flint
authors: MF
authors: Beal
authors: Mahmoud
authors: M
authors: Kiaei
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D033921:Vesicular Transport Proteins
chemical_list: C568680:(2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) trifluoroethylamide; C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins; C485462:Vps52 protein, mouse; D009828:Oleanolic Acid; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase