Toll-Like Receptor 4 Antagonist Attenuates Intracerebral Hemorrhage-Induced Brain Injury
Toll-Like Receptor 4 Antagonist Attenuates Intracerebral Hemorrhage-Induced Brain Injury
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DOI：
10.1161/strokeaha.113.001038
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发表时间：
2013-09-01
期刊：
影响因子：
8.3
通讯作者：
Yang, Qing-Wu
中科院分区：
文献类型：
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作者：
Wang, Yan-Chun;Wang, Peng-Fei;Yang, Qing-Wu
背景和目的越来越多的证据表明脑出血后炎症反应导致继发性损伤。我们最近证明了Toll样受体4（TLR 4）信号转导在这些过程中的参与。本研究的目的是探讨TAK-242（（6 R）-6-[N-（2-氯-4-氟苯基）氨磺酰基]环己-1-烯-1-羧酸乙酯，武田），一种TLR 4拮抗剂，在ICH小鼠模型中的保护作用和机制。我们评估了神经功能缺损评分;脑含水量的变化;以及ICH后1、3和5天血肿周围区域的炎症因子、DNA损伤和神经元变性水平。采用流式细胞术测定外周炎性细胞浸润，并通过Western blot评估TLR 4下游信号分子的表达。结果TAK-242可显著降低脑含水量、神经功能缺损评分和炎性因子水平。DNA损伤和神经元变性的水平也显著降低，外周炎性细胞浸润也显著降低。TLR 4下游信号分子的表达，包括髓样分化的主要反应基因88，toll/IR-1（TIR）-域的衔接蛋白诱导干扰素β IB，核因子Bp 65，磷酸化核因子Bp 65，是显着下调。结论表明，TLR 4拮抗剂减少炎症损伤和神经功能缺损的小鼠模型的ICH。其机制可能涉及TLR 4下游信号分子表达的减少。
Background and Purpose Accumulating evidence indicates that inflammatory responses cause secondary injury after intracerebral hemorrhage (ICH). We recently demonstrated the involvement of toll-like receptor 4 (TLR4) signaling in these processes. The purpose of the current study was to investigate the protective effect and mechanism of TAK-242 (Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1 -carboxylate, Takeda), a TLR4 antagonist, in an ICH mouse model.Methods TAK-242 was intraperitoneally injected 6 hours after ICH once daily for 5 successive days. We assessed neurological deficit scores; changes in brain water content; and levels of inflammatory factors, DNA damage, and neuronal degeneration in perihematomal region 1, 3, and 5 days after ICH. Peripheral inflammatory cell infiltration was determined using flow cytometry; and the expression of TLR4 downstream signaling molecules was assessed by Western blot.Results TAK-242 significantly reduced brain water content, neurological deficit scores, and levels of inflammatory factors. The levels of DNA damage and neuronal degeneration were also significantly decreased, as was peripheral inflammatory cell infiltration. The expression of TLR4 downstream signaling molecules, including myeloid differentiation primary response gene 88, toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta IB, nuclear factor-Bp65, and phosphorylated nuclear factor-Bp65, was significantly downregulated.Conclusions The results suggest that TLR4 antagonist reduced inflammatory injury and neurological deficits in a mouse model of ICH. The mechanism may involve decreased expression of signaling molecules downstream of TLR4.