Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition
Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition
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DOI：
10.1016/j.freeradbiomed.2015.03.003
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发表时间：
2015-07-01
影响因子：
7.4
通讯作者：
Peng, Jinyong
中科院分区：
文献类型：
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作者：
Tao, Xufeng;Sun, Xiance;Peng, Jinyong
我们以前报道了薯蓣皂苷对肝脏缺血/再灌注（I/R）损伤的有希望的作用，但其对脑I/R损伤的影响尚不清楚。在这项工作中，在体外的氧-葡萄糖剥夺和复氧（OGD/R）模型和在体内的大脑中动脉闭塞（MCAO）模型。结果表明，薯蓣皂苷明显保护PC 12细胞和原代皮层神经元免受OGD/R损伤，并显著防止脑I/R损伤。进一步的研究表明，薯蓣皂苷诱导的神经保护伴随着HMGB-1的表达和核向胞质易位的显著抑制，反映为TLR 4表达的降低。薯蓣皂苷阻断TLR 4/MyD 88/TRAF 6信号通路可抑制NF-κ B和AP-1转录活性、MAPK和STAT 3磷酸化以及促炎细胞因子反应，并上调抗炎因子水平。此外，分别应用小干扰RNA（siRNA）和HMGB-1/TLR 4过表达基因进行体外实验，结果进一步证实薯蓣皂苷通过抑制HMGB-1/TLR 4信号通路进而抑制炎症反应而表现出有效的神经保护作用。这些发现提供了新的见解，将有助于阐明薯蓣皂苷对脑I/R损伤的影响，并支持薯蓣皂苷作为缺血性卒中潜在治疗方法的发展。(C)2015 Elsevier Inc. All rights reserved.
We previously reported the promising effect of dioscin against hepatic ischemia/reperfusion (I/R) injury, but its effect on cerebral I/R injury remains unknown. In this work, an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) model were used. The results indicated that dioscin clearly protected PC12 cells and primary cortical neurons against OGD/R insult and significantly prevented cerebral I/R injury. Further research demonstrated that dioscin-induced neuroprotection was accompanied by a significant inhibition in the expression and the nuclear to cytosolic translocation of HMGB-1, reflected by decreased TLR4 expression. Blockade of the TLR4/MyD88/TRAF6 signaling pathway by dioscin inhibited NF-kappa B and AP-1 transcriptional activities, MAPK and STAT3 phosphorylation, and pro-inflammatory cytokine responses, and upregulated the levels of anti-inflammatory factors. In addition, small interfering RNA (siRNA) and overexpressed genes of HMGB-1 and TLR4 were applied in in vitro experiments, respectively, and the results further confirmed that dioscin showed an efficient neuroprotection because of its inhibiting effects on HMGB-1/TLR4 signaling and subsequent suppressing inflammation. These findings provide new insights that will aid in elucidating the effect of dioscin against cerebral I/R injury and support the development of dioscin as a potential treatment for ischemic stroke. (C) 2015 Elsevier Inc. All rights reserved.