TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice.
TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice.
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TAK-242 是 Toll 样受体 4 的拮抗剂，可预防小鼠急性脑缺血/再灌注损伤。
DOI：
10.1038/jcbfm.2014.240
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发表时间：
2015-03-31
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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Toll样受体4（TLR 4）参与脑缺血/再灌注（I/R）损伤，是治疗缺血性卒中的潜在靶点。本实验旨在评价外源性TLR 4拮抗剂TAK-242对急性脑I/R损伤的作用。通过短暂性大脑中动脉闭塞诱导小鼠脑I/R模型。在缺血后1小时腹膜内注射TAK-242（3 mg/kg体重）。我们的结果表明，TAK-242的血浆浓度在注射后3小时升高至52.0 ng/mL，在注射后8小时维持在54.1 ng/mL，在注射后24小时降低至22.6 ng/mL。注射后3小时，脑组织中TAK-242的浓度在缺血半球中增加至26.1 ng/mL，在非缺血半球中增加至14.2 ng/mL，并在注射后24小时维持在相似水平。我们发现，与溶剂对照组相比，TAK-242可显著减少脑梗死，改善神经功能，抑制TLR 4信号通路下游蛋白激酶的磷酸化，并下调炎性细胞因子的表达。我们得出结论，TAK-242能够穿过血脑屏障，阻断TLR 4信号传导，介导炎性细胞因子的表达，并保护脑免受I/R诱导的急性损伤。
Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.
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影响因子：
8.3
作者：
GARCIA, JH;WAGNER, S;HU, XJ
通讯作者：
HU, XJ
DOI：
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发表时间：
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作者：
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作者：
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