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
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
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天麻异钩藤碱通过靶向 ERK1/2 和 GSK-3β 途径协同抑制 MPP 诱导的 SH-SY5Y 细胞氧化应激：参与 Nrf2 核易位
DOI：
10.1021/acschemneuro.7b00247
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发表时间：
2018-03-01
影响因子：
5
通讯作者：
Dong, Miaoxian
中科院分区：
文献类型：
--
作者：
Li, Qiang;Niu, Chengu;Dong, Miaoxian
帕金森氏病（PD）的发病机理是多因素事件。联合疗法可能在控制该疾病方面更有效。因此，设计的研究旨在检验以下假设：胃诱导的核因子E2相关因子2（NRF2）的从头合成（NRF2）和isorhynchophophophophophophophyline（IRN）抑制NRF2核出口有助于其添加剂或协同神经保护效应。在这里，我们已经证明了气体和IRN（气/IRN）的组合以协同的方式保护SH-Sysy细胞免受1-甲基-4-苯基吡啶丹（MPP+）毒性的毒性。同时，气体/IRN导致氧化应激的统计学显着减少，这是由活性氧（ROS）和脂质氢过氧化物（LPO）评估的，以及与谷胱甘肽（GSH）和硫糖蛋白（TRX）系统的增强相比，与与治疗相比的增强单独使用MPP+挑战的SH-SY5Y细胞中的代理。有趣的是，气体而不是IRN激活了细胞外信号调节的激酶1和2（ERK1/2），从而导致NRF2的从头合成和NRF2的核进口增加。同时，IRN而非气体抑制了本构糖原合酶激酶（GSK）-3β和FYN激活，它们抑制了NRF2的核出口。重要的是，通过IRN同时抑制GSK-3 BetA途径，并通过气体在受MPP+质疑的SH-SY5Y细胞中通过气体协同诱导NRF2的ERK1/2途径激活ERK1/2途径。此外，ERK1/2途径的激活和通过气体/IRN抑制GSK-3β途径的激活是由独立机制介导的。总的来说，这些新颖的发现表明，在诱导神经保护作用中，IRN和气体之间的协同作用模型需要在体内进一步研究。
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-SYSY 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)-3 beta and Fyn activation, which inhibited nuclear export of Nrf2. Importantly, simultaneous inhibition of GSK-3 beta 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-3 beta 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.