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Gastrodin and Isorhynchophylline Synergistically Inhibit MPP+-Induced Oxidative Stress in SH-SY5Y Cells by Targeting ERK1/2 and GSK-3β Pathways: Involvement of Nrf2 Nuclear Translocation
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2017-11-08 00:00:00 , DOI: 10.1021/acschemneuro.7b00247
Qiang Li 1 , Chengu Niu 2 , Xiaojie Zhang 1 , Miaoxian Dong 1
Affiliation  

The pathogenesis of Parkinson’s disease (PD) is multifactorial event. Combination therapies might be more effective in controlling the disease. Thus, the studies reported were designed to test the hypothesis that gastrodin (GAS)-induced de novo synthesis of nuclear factor E2-related factor 2 (Nrf2) and isorhynchophylline (IRN) inhibition of Nrf2 nuclear export contribute to their additive or synergistic neuroprotective effect. Here, we have demonstrated that the combination of GAS and IRN (GAS/IRN) protects SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+) toxicity in a synergistic manner. Concomitantly, GAS/IRN led to a statistically significant reduction of oxidative stress, as assessed by reactive oxygen species (ROS) and lipid hydroperoxides (LPO), and enhancement of both glutathione (GSH) and thioredoxin (Trx) systems compared with treatment with either agent alone in MPP+-challenged SH-SY5Y cells. Interestingly, GAS but not IRN activated extracellular signal-regulated kinases 1 and 2 (ERK1/2), leading to a increase in de novo synthesis of Nrf2 and nuclear import of Nrf2. Simultaneously, IRN but not GAS suppressed both constitutive glycogen synthase kinase (GSK)-3β and Fyn activation, which inhibited nuclear export of Nrf2. Importantly, simultaneous inhibition of GSK-3β pathway by IRN and activation of ERK1/2 pathway by GAS synergistically induced accumulation of Nrf2 in the nucleus in SH-SY5Y cells challenged with MPP+. Furthermore, the activation of the ERK1/2 pathway and inhibition of GSK-3β pathway by GAS/IRN are mediated by independent mechanisms. Collectively, these novel findings suggest an in vitro model of synergism between IRN and GAS in the induction of neuroprotection warrant further investigations in vivo.

中文翻译:

天麻素和异麦角茶碱通过靶向ERK1 / 2和GSK-3β途径协同抑制SH-SY5Y细胞中MPP +诱导的氧化应激:Nrf2核易位的参与。

帕金森氏病(PD)的发病机制是多因素事件。组合疗法可能在控制疾病方面更有效。因此,所报道的研究旨在检验以下假设:天麻素(GAS)诱导的核因子E2相关因子2(Nrf2)的从头合成和异叶茶碱(IRN)抑制Nrf2核输出有助于它们的累加或协同神经保护作用。在这里,我们证明了GAS和IRN(GAS / IRN)的组合可保护SH-SY5Y细胞免受1-甲基-4-苯基吡啶鎓(MPP +)协同作用的毒性。同时,通过活性氧(ROS)和脂质氢过氧化物(LPO)评估,GAS / IRN导致氧化应激在统计学上显着降低,并且与其中任一种处理相比,谷胱甘肽(GSH)和硫氧还蛋白(Trx)系统均得到增强MPP +中单独代理挑战的SH-SY5Y细胞。有趣的是,GAS而非IRN激活了细胞外信号调节激酶1和2(ERK1 / 2),从而导致Nrf2的从头合成增加和Nrf2的核输入增加。同时,IRN而非GAS抑制组成型糖原合酶激酶(GSK)-3β和Fyn活化,从而抑制Nrf2的核输出。重要的是,IRP同时抑制GSK-3β途径,GAS协同诱导MPR +攻击的SH-SY5Y细胞核中Nrf2积累,从而激活ERK1 / 2途径。。此外,GAS / IRN对ERK1 / 2途径的激活和对GSK-3β途径的抑制是由独立的机制介导的。总的来说,这些新发现提示IRN和GAS在诱导神经保护中的协同作用的体外模型值得进一步的体内研究。
更新日期:2017-11-08
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