Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis.
Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis.
复制标题
NRF2/是激活剂，CDDO乙酰胺和CDDO三氟乙酰胺的神经保护作用，在肌萎缩性侧面硬化症的小鼠模型中。
DOI：
10.1016/j.freeradbiomed.2011.03.027
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发表时间：
2011-07-01
影响因子：
7.4
通讯作者：
Kiaei, Mahmoud
中科院分区：
文献类型：
--
作者：
Neymotin, Arie;Calingasan, Noel Y.;Wille, Elizabeth;Naseri, Nima;Petri, Susanne;Damiano, Maria;Liby, Karen T.;Risingsong, Renee;Sporn, Michael;Beal, M. Flint;Kiaei, Mahmoud
氧化损伤、神经炎症和线粒体功能障碍是ALS的发病机制，这些病理过程受到Nrf 2/ARE（NF-E2 related factor 2/antioxidant response element，NF-E2相关因子2/抗氧化反应元件）信号转导程序的密切调控。因此，Nrf 2/ARE通路的调节是神经退行性疾病如ALS的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-3，12-二氧代齐墩果-1，9-二烯-28-酸）乙酰胺（CDDO-EA）和CDDO-三氟乙酰胺（CDDO-TFEA），它们在ALS的细胞培养模型和ALS的G93 A SOD 1小鼠模型中有效地激活Nrf 2/ARE。用CDDO-TFEA处理稳定表达突变型G93 A SOD 1的NSC-34细胞上调Nrf 2表达，并导致Nrf 2易位到细胞核中。Western blot分析显示Nrf 2/ARE调节蛋白的表达增加。当在“症状前年龄”（30天）开始治疗时，这两种化合物均显著减轻了G93 A SOD 1小鼠的体重减轻，增强了运动表现并延长了存活期。治疗开始于“症状年龄”，如通过运动功能受损评估的，具有神经保护作用并减缓疾病进展。这些发现进一步证明了激活Nrf 2/ARE信号通路的化合物可用于治疗ALS。
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.
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DOI：
10.1073/pnas.88.16.7276
发表时间：
1991-08-01
影响因子：
11.1
作者：
HOLLAND, PM;ABRAMSON, RD;GELFAND, DH
通讯作者：
GELFAND, DH
DOI：
10.1073/pnas.0607260103
发表时间：
2006-10-10
影响因子：
11.1
作者：
Clements, Casey M.;McNally, Richard S.;Ting, Jenny P-Y.
通讯作者：
Ting, Jenny P-Y.
影响因子：
5.3
作者：
Derjuga, A;Gourley, TS;Blank, V
通讯作者：
Blank, V
影响因子：
3
作者：
Haastert, K;Grosskreutz, J;Claus, P
通讯作者：
Claus, P
影响因子：
4.7
作者：
Kiaei, M;Kipiani, K;Beal, MF
通讯作者：
Beal, MF