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

Free Radic Biol Med. 2011 Jul 1;51(1):88-96. doi: 10.1016/j.freeradbiomed.2011.03.027. Epub 2011 Mar 30.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Cell Line
  • Cell Nucleus / enzymology
  • Disease Models, Animal
  • Inflammation / metabolism
  • Major Histocompatibility Complex / genetics
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism
  • NF-E2-Related Factor 2 / biosynthesis
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Neurodegenerative Diseases / genetics
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / metabolism
  • Oleanolic Acid / pharmacology
  • Oleanolic Acid / therapeutic use
  • Oxidative Stress
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger / biosynthesis
  • Signal Transduction
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics
  • Vesicular Transport Proteins

Substances

  • (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) trifluoroethylamide
  • 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Proteins
  • RNA, Messenger
  • Vesicular Transport Proteins
  • Vps52 protein, mouse
  • Oleanolic Acid
  • SOD1 G93A protein
  • Superoxide Dismutase