Ligustroflavone reduces necroptosis in rat brain after ischemic stroke through targeting RIPK1/RIPK3/MLKL pathway
Ligustroflavone reduces necroptosis in rat brain after ischemic stroke through targeting RIPK1/RIPK3/MLKL pathway
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女贞子黄酮通过靶向 RIPK1/RIPK3/MLKL 通路减少缺血性中风后大鼠脑坏死性凋亡
DOI：
10.1007/s00210-019-01656-9
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发表时间：
2019-05
期刊：
影响因子：
--
通讯作者：
Peng Jun
中科院分区：
文献类型：
--
作者：
Zhang Yi Yue;Liu Wei Ning;Li Yue Qi;Zhang Xiao Jie;Yang Jie;Luo Xiu Ju;Peng Jun
受体相互作用蛋白激酶1/3（RIPK 1/3）和混合谱系激酶结构域样（MLKL）介导的坏死性凋亡促进缺血性卒中后的脑损伤。女贞子黄酮是女贞子中的一种成分，具有抗炎和抑制补体的作用。本研究旨在探讨女贞子黄酮对脑卒中大鼠缺血性脑损伤的影响及其机制。通过大脑中动脉闭塞（MCAO）建立缺血性卒中大鼠模型，其显示缺血性损伤（神经功能缺损评分和梗死体积增加）和坏死性凋亡相关蛋白（RIPK 1、RIPK 3和MLKL/p-MLKL）的上调。给药女贞子黄酮（30 mg/kg，i.g.）缺血前15 min组神经功能明显改善，梗死体积缩小，除RIPK 1外，其他坏死性凋亡相关蛋白水平均降低。结果表明，缺氧（O2/N2/CO2，1：94：5，8 h）培养的PC 12细胞出现LDH释放和坏死，并伴随着坏死相关蛋白的上调，而这些现象在女贞子黄酮（25 μM）的存在下被阻断，但RIPK 1水平升高。使用分子操作环境（莫伊）程序，我们确定RIPK 1，RIPK 3和MLKL作为女贞子黄酮的潜在靶标。进一步的研究表明，RIPK 3与RIPK 1或MLKL之间的相互作用显著增强，在女贞子黄酮的存在下，这种相互作用被阻断。基于这些观察结果，我们得出结论，女贞子黄酮保护大鼠脑缺血损伤，其有益效果是通过涉及靶向RIPK 1，RIPK 3和/或MLKL的机制来预防坏死性凋亡。
Receptor-interacting protein kinase 1/3 (RIPK1/3) and mixed lineage kinase domain-like (MLKL)-mediated necroptosis contributes to brain injury after ischemic stroke. Ligustroflavone is an ingredient ofcommon privetwith activities of anti-inflammation and complement inhibition. This study aims to explore the effect of ligustroflavone on ischemic brain injury in stroke rat and the underlying mechanisms. A rat model of ischemic stroke was established by middle cerebral artery occlusion (MCAO), which showed ischemic injury (increase in neurological deficit score and infarct volume) and upregulation of necroptosis-associated proteins (RIPK1, RIPK3 and MLKL/p-MLKL). Administration of ligustroflavone (30 mg/kg, i.g.) 15 min before ischemia evidently improved neurological function, reduced infarct volume, and decreased the levels of necroptosis-associated proteins except the RIPK1. Consistently, hypoxia-cultured PC12 cells (O2/N2/CO2, 1:94:5, 8 h) caused cellular injury (LDH release and necroposis) concomitant with up-regulation of necroptosis-associated proteins, and these phenomena were blocked in the presence of ligustroflavone (25 μM) except the elevated RIPK1 levels. Using the Molecular Operating Environment (MOE) program, we identified RIPK1, RIPK3, and MLKL as potential targets of ligustroflavone. Further studies showed that the interaction between RIPK3 and RIPK1 or MLKL was significantly enhanced, which was blocked in the presence of ligustroflavone. Based on these observations, we conclude that ligustroflavone protects rat brain from ischemic injury, and its beneficial effect is related to the prevention of necroptosis through a mechanism involving targeting RIPK1, RIPK3, and/or MLKL.
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