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 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.

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

“…12 To further study the involvement of Nrf2 pathway in the process of motor neuron degeneration in SOD1-G93A mice, we generated double mutant mice, Nrf2 À / À SOD1-G93A, by mating SOD1-G93A mice to Nrf2 À / À animals with the same genetic background. The Nrf2 gene knockout was confirmed by PCR examination (Figure 2a).…”

“…10,11 In this context, several studies demonstrated that Nrf2/ARE activators provided robust neuroprotective effect and ameliorated the disease progression in SOD1-G93A transgenic mice. 12,13 Notably, upregulation of Nrf2 expression was found in the nucleus of motor neurons in lumbar anterior horn of ALS model mice. 14 We also reported that significant HO-1 induction was detected in the lumbar spinal cord of ALS mice.…”

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

“…CDDO-MA also improves spatial memory and reduces the number and size of amyloid plaques in the hippocampus in a model of Alzheimer's disease in which mice carry two mutations in the human amyloid precursor protein (Dumont et al, 2009). Compared with CDDO-MA, higher drug levels of CDDO-EA and CDDO-TFEA can be obtained in the brain, and both of these amides prolong survival in transgenic mouse models of Huntington's disease (Stack et al, 2010) and ALS (Neymotin et al, 2011). Even when treatment is delayed until the onset of motor symptoms in G93A SOD1 mice, the SOs slow progression of ALS and extend the lifespan of these mice (Neymotin et al, 2011).…”

Insights Arising from Gene Expression Profiling in Amyotrophic Lateral Sclerosis

“…Subsequent work by Sarlette and colleagues has shown that NRF2 transcription and translation is also decreased in SALS cases (Sarlette et al 2008). Most recently, it has been demonstrated that activation of Nrf2 in NSC34 SOD1-related ALS cell models, primary motor neurone and astrocyte co-cultures and in the SOD1 G93A mouse model all improve neuronal survival (Neymotin et al 2011;Vargas et al 2008a). Primary astrocyte cultures prepared from mutant SOD1 rodent models have been shown to increase motor neuronal death in co-cultures (Nagai et al 2007;Vargas et al 2006).…”