Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF-A-mediated transactivity
Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF-A-mediated transactivity
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DOI：
10.1016/j.ejphar.2015.10.027
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发表时间：
2015-11-15
影响因子：
5
通讯作者：
Hu, Xia-min
中科院分区：
文献类型：
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作者：
Zheng, Wen-xia;Cao, Xiao-lu;Hu, Xia-min
黄芩苷具有减轻脑缺血损伤的神经保护作用。然而，人们对其潜在机制知之甚少。本实验通过建立脑动脉闭塞(MACO)/再灌注大鼠模型和过氧化氢（H202）处理的大鼠皮层原代神经元培养，观察黄芩苷对缺血诱导的神经元凋亡的影响。我们发现黄芩苷能显著减少神经功能缺损，减少脑梗死体积。在体内和体外均能有效抑制神经元凋亡，尤其表现为增强髓样细胞白血病-1 （MCL-1）和b细胞淋巴瘤-2 （BCL-2）的转录和表达，且呈剂量依赖性。黄芩苷可显著提高缺血半球和原代皮层神经元中心肌素相关转录因子- a （MRTF-A）的表达水平，而转染MRTF-A小干扰RNA （MRTF-A siRNA）可显著抑制黄芩苷的抗凋亡作用。荧光素酶实验还显示黄芩苷通过激活被MRTF-A siRNA还原的关键CArG盒（CC [A/TI 6GG）元件增强MCL-1和BCL-2启动子的交互活性，提示MRTF-A可能参与了黄芩苷的抗凋亡作用，参与了黄芩苷诱导的MCL-1和BCL-2的转录活性。LY294002（磷脂酰肌醇-3激酶（PI3K）抑制剂）和PD98059（细胞外信号调节激酶-1/2 （ERK1/2）抑制剂）明显降低黄芩苷诱导的MRTF-A表达、MCL-1和BCL-2的交互活性和表达，进一步消除黄芩苷对神经元凋亡的抗凋亡作用。综上所述，我们的数据提供了黄芩苷神经保护作用的证据，部分原因是由于mrtf - a通过触发CArG盒介导MCL-1和BCL-2的交易性和表达，这可能是由PI3K和ERK1/2的激活控制的。(C) 2015 Elsevier B.V.版权所有
Baicalin has been shown to provide the neuroprotective effect by alleviating cerebral ischemia injury. However, little's known about the underlying mechanism. Here, a cerebral artery occlusion (MACO)/ reperfusion rat model and rat primary cortical neuron culture exposed to hydrogen peroxide (H202) were established to evaluate the effect of baicalin on ischemia-induced neuronal apoptosis. We found baicalin can significantly less neurological deficit and reduced infarct volume in vivo. And it efficiently inhibited neuronal apoptosis in vivo and vitro, which was especially characterized by the enhancing of transcription and expression of myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma-2 (BCL-2) in a dose-dependent manner. Furthermore, Baicalin markedly increased myocardin-related transcription factor-A (MRTF-A) level either in ischemic hemisphere or in primary cortical neuron cultures, whiles the antiapoptosis effect of baicalin was significantly inhibited by transfected with the small interfering RNA of MRTF-A (MRTF-A siRNA) in primary cortical neuron cultures. The luciferase assays also indicated baicalin enhanced the transactivity of MCL-1 and BCL-2 promoter by activating the key CArG box (CC [A/TI 6GG) element, which was reduced by MRTF-A siRNA, suggesting MRTF-A may participate the anti-apoptosis effect of baicalin, and MRTF-A was involved in the transcriptional activity of MCL-1 and BCL-2 that was induced by baicalin. LY294002 (phosphatidylinositol-3 kinase (PI3K) inhibitor) and PD98059 (extracellular signal regulates kinase-1/2 (ERK1/2) inhibitor) obviously reduced baicalin-induced MRTF-A expression and transactivity and expression of MCL-1 and BCL-2, which further abolished the anti-apoptotic effect of baicalin on neuronal apoptosis. Taken together, our data provided the evidence demonstrating the neuroprotective effect of baicalin partially due to MRTF-A-mediated transactivity and expression of MCL-1 and BCL-2 by triggering the CArG box, which might be controlled by the activation of PI3K and ERK1/2. (C) 2015 Elsevier B.V. All rights reserved.