Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK
Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK
复制标题
Fisetin 通过激活 ERK 在肌萎缩侧索硬化症的多种 hSOD1 突变模型中发挥抗氧化和神经保护作用
DOI：
10.1016/j.neuroscience.2018.03.008
复制
发表时间：
2018-05
期刊：
影响因子：
3.3
通讯作者：
Feng H. L.
中科院分区：
文献类型：
--
作者：
Wang T. H.;Wang S. Y.;Wang X. D.;Jiang H. Q.;Yang Y. Q.;Wang Y.;Cheng J. L.;Zhang C. T.;Liang W. W.;Feng H. L.
氧化应激在肌萎缩侧索硬化症 (ALS) 的病程中发挥着核心作用，这是一种进行性神经退行性疾病，通常发现包括铜/锌超氧化物歧化酶 (SOD1) 基因突变。非瑟酮是一种天然抗氧化剂，已显示出对多种神经退行性疾病的益处。迄今为止，非瑟酮对 ALS 的可能作用尚未明确。我们研究了非瑟酮是否影响突变 hSOD1 ALS 模型。使用三种不同的hSOD1相关突变模型：表达突变hSOD1G85R的果蝇、hSOD1G93ANSC34细胞和转基因小鼠。与对照组相比，非瑟酮治疗提供了神经保护作用，提高了存活率，减轻了运动损伤，减少了 ROS 损伤并调节了氧化还原稳态。此外，非瑟酮可增加磷酸化 ERK 的表达并上调抗氧化因子，而 MEK/ERK 抑制可逆转这一现象。最后，非瑟酮在体内和体外降低了突变型和野生型 hSOD1 的水平，以及去污剂不溶性 hSOD1 蛋白的水平。结果表明，非瑟酮可能通过激活ERK来保护细胞免受ROS损伤，并改善SOD1基因突变相关疾病模型中氧化应激引起的病理行为，从而为ALS提供潜在的治疗方法。
Oxidative stress exhibits a central role in the course of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease commonly found to include a copper/zinc superoxide dismutase (SOD1) gene mutation. Fisetin, a natural antioxidant, has shown benefits in varied neurodegenerative diseases. The possible effect of fisetin in ALS has not been clarified as of yet. We investigated whether fisetin affected mutant hSOD1 ALS models. Three different hSOD1-related mutant models were used:Drosophilaexpressing mutant hSOD1G85R, hSOD1G93ANSC34 cells, and transgenic mice. Fisetin treatment provided neuroprotection as demonstrated by an improved survival rate, attenuated motor impairment, reduced ROS damage and regulated redox homeostasis compared with those in controls. Furthermore, fisetin increased the expression of phosphorylated ERK and upregulated antioxidant factors, which were reversed by MEK/ERK inhibition. Finally, fisetin reduced the levels of both mutant and wild-type hSOD1in vivo and in vitro, as well as the levels of detergent-insoluble hSOD1 proteins. The results indicate that fisetin protects cells from ROS damage and improves the pathological behaviors caused by oxidative stress in disease models related to SOD1 gene mutations probably by activating ERK, thereby providing a potential treatment for ALS.
登录
查看更多内容
影响因子：
3.7
作者：
Ikeda K;Iwasaki Y
通讯作者：
Iwasaki Y
DOI：
10.1534/g3.113.005850
发表时间：
2013-04-09
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Kumimoto EL;Fore TR;Zhang B
通讯作者：
Zhang B
影响因子：
15.1
作者：
Prudencio M;Borchelt DR
通讯作者：
Borchelt DR
影响因子：
7.4
作者：
D'Amico, Emanuele;Factor-Litvak, Pam;Santella, Regina M.;Mitsumoto, Hiroshi
通讯作者：
Mitsumoto, Hiroshi
影响因子：
4.8
作者：
Kabuta, Tomohiro;Suzuki, Yasuyuki;Wada, Keiji
通讯作者：
Wada, Keiji