4-Ethylguaiacol Modulates Neuroinflammation and Promotes Heme Oxygenase-1 Expression to Ameliorate Brain Injury in Ischemic Stroke.
4-Ethylguaiacol Modulates Neuroinflammation and Promotes Heme Oxygenase-1 Expression to Ameliorate Brain Injury in Ischemic Stroke.
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4-乙基愈创木酚调节神经炎症并促进血红素加氧酶-1的表达，从而改善缺血性脑卒中的脑损伤。
DOI：
10.3389/fimmu.2022.887000
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发表时间：
2022
影响因子：
7.3
通讯作者：
Yen, Jui-Hung
中科院分区：
文献类型：
--
作者：
Weng, Wen-Tsan;Kuo, Ping-Chang;Scofield, Barbara A.;Paraiso, Hallel C.;Brown, Dennis A.;Yu, I-Chen;Yen, Jui-Hung
缺血性中风是由脑血流量突然减少引起的，随后诱导复杂的级联病理生理反应，导致脑炎症和不可逆的梗死。4-据报道乙基愈创木酚（4-EG）抑制炎性免疫应答。然而，4-EG是否在缺血性卒中中发挥抗炎作用仍有待研究。我们评估了4-EG的治疗潜力，并研究了4-EG在缺血性卒中中保护作用的细胞和分子机制。通过使用短暂性大脑中动脉闭塞（MCAO）动物模型，随后探索梗死面积、神经功能缺损、小胶质细胞活化、炎性细胞因子产生、血脑屏障（BBB）破坏、脑内皮细胞粘附分子表达和小胶质细胞血红素加氧酶-1（HO-1）表达，确定4-EG在缺血性卒中中的作用。Nrf 2-/-和HO-1抑制剂ZnPP处理的小鼠也经历MCAO以评估Nrf 2/HO-1通路在缺血性中风中4-EG介导的保护中的作用。我们发现，4-EG减轻了缺血性卒中的梗死面积和神经功能缺损，并减少了血脑屏障破坏。进一步的研究表明，4-EG抑制缺血脑中小胶质细胞活化、外周炎性免疫细胞浸润和脑内皮细胞粘附分子上调。最后，我们确定了4-EG在缺血性中风中的保护作用在Nrf 2-/-和ZnPP处理的MCAO小鼠中被消除。我们的研究结果表明，4-EG赋予对缺血性中风的保护作用，并揭示4-EG在缺血性中风中的保护作用是通过诱导Nrf 2/HO 1通路介导的。因此，我们的研究结果表明，4-EG可以开发为一种新的治疗剂，用于治疗缺血性中风。
Ischemic stroke is caused by a sudden reduction in cerebral blood flow that subsequently induces a complex cascade of pathophysiological responses, leading to brain inflammation and irreversible infarction. 4-ethylguaiacol (4-EG) is reported to suppress inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects in ischemic stroke remains unexplored. We evaluated the therapeutic potential of 4-EG and examined the cellular and molecular mechanisms underlying the protective effects of 4-EG in ischemic stroke. The effect of 4-EG in ischemic stroke was determined by using a transient middle cerebral artery occlusion (MCAO) animal model followed by exploring the infarct size, neurological deficits, microglia activation, inflammatory cytokine production, blood–brain barrier (BBB) disruption, brain endothelial cell adhesion molecule expression, and microglial heme oxygenase-1 (HO-1) expression. Nrf2-/- and HO-1 inhibitor ZnPP-treated mice were also subjected to MCAO to evaluate the role of the Nrf2/HO-1 pathway in 4-EG-mediated protection in ischemic stroke. We found that 4-EG attenuated infarct size and neurological deficits, and lessened BBB disruption in ischemic stroke. Further investigation revealed that 4-EG suppressed microglial activation, peripheral inflammatory immune cell infiltration, and brain endothelial cell adhesion molecule upregulation in the ischemic brain. Finally, we identified that the protective effect of 4-EG in ischemic stroke was abolished in Nrf2-/– and ZnPP-treated MCAO mice. Our results identified that 4-EG confers protection against ischemic stroke and reveal that the protective effect of 4-EG in ischemic stroke is mediated through the induction of the Nrf2/HO1 pathway. Thus, our findings suggest that 4-EG could be developed as a novel therapeutic agent for the treatment of ischemic stroke.
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