Oxidative damage, neuroinflammation, and mitochondrial dysfunction contribute to the pathogenesis of 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 (CDDO-EA) 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 30 days 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 which activate the Nrf2/ARE signaling pathway may be useful in the treatment of ALS.

Background and aims Nanoparticles could represent a therapeutic approach for the treatment of various diseases. It has been reported that cerium oxide nanoparticles (CeO 2 NPs) have potential useful effects. Therefore, we aimed to examine the protective effects of the CeO 2 NPs in two models of liver injury, non-alcoholic fatty liver disease (NAFLD) and carbon tetrachloride (CCl 4 )-induced liver fibrosis, in rats. Methods In this experimental study, male rats were randomly divided into different experimental groups including: Experiment 1; group1: healthy rats received normal saline, 2: CCl 4 group, 3: CCl 4 + nanoparticle. Experiment 2; group1: healthy rats received chow diet, 2: NAFLD group, 3: NAFLD + nanoparticle. The oxidative stress markers were determined in the liver and intestine. Tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Histopathological changes of liver and intestine were evaluated by light microspore. Results Total antioxidant capacity (TAC) and glutathione (GSH) levels significantly decreased, while malondialdehyde (MDA) and total oxidant status (TOS) were significantly increased in the liver, and intestine of the NAFLD and CCl 4 group compared with control rats. However, the use of nanoparticles significantly normalized these markers. The levels of the TNF-α were significantly reduced in the nanoparticle group as compared with NAFLD model and CCl 4 -treated rats. CeO 2 NPs also normalized the liver and intestinal histological changes. Conclusions Our finding revealed that CeO 2 NPs has potential protective effects by increasing antioxidant activity, and reducing inflammation.