Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA.
Free Radic Biol Med. 2011 Jul 1;51(1):88-96. doi: 10.1016/j.freeradbiomed.2011.03.027. Epub 2011 Mar 30.
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.
氧化损伤、神经炎症和线粒体功能障碍导致肌萎缩侧索硬化症（ALS）的发病机制，这些病理过程受 Nrf2/ARE（NF-E2 相关因子 2/抗氧化反应元件）信号通路的严格调控。因此，调节 Nrf2/ARE 通路是治疗 ALS 等神经退行性疾病的一个有吸引力的治疗靶点。我们研究了两种三萜类化合物，CDDO（2-氰基-3,12-二氧代-1,9-二烯-28-酸乙酯）和 CDDO 三氟乙酯（CDDO-TFEA），它们在 ALS 的细胞培养模型中和 G93A SOD1 小鼠 ALS 模型中能强烈激活 Nrf2/ARE。用 CDDO-TFEA 处理稳定表达突变型 G93A SOD1 的 NSC-34 细胞，上调 Nrf2 的表达，并导致 Nrf2 向核内易位。Western blot 分析显示 Nrf2/ARE 调节蛋白的表达增加。当治疗从 30 天的“无症状期”开始时，这两种化合物都显著减轻了体重减轻、增强了运动性能，并延长了 G93A SOD1 小鼠的寿命。从运动性能受损的“症状期”开始治疗具有神经保护作用并减缓疾病进展。这些发现进一步证明，激活 Nrf2/ARE 信号通路的化合物可能对治疗 ALS 有用。
