THE NOVEL SELECTIVE TOLL-LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK-242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA-PIGS
THE NOVEL SELECTIVE TOLL-LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK-242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA-PIGS
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DOI：
10.1111/j.1440-1681.2008.05121.x
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发表时间：
2009-05-01
影响因子：
2.9
通讯作者：
Yokota, Hiroyuki
中科院分区：
文献类型：
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作者：
Kuno, Masamune;Nemoto, Kayo;Yokota, Hiroyuki
TAK-242 是一种新型化合物，通过选择性抑制 Toll 样受体 (TLR)-4 的细胞内信号来抑制一氧化氮和细胞因子的产生。在本研究中，我们使用内毒素血症模型在清醒和不受限制的豚鼠中研究了 TAK-242 对抗脓毒症的有效性。检查的指标包括肠道肌张力麻痹、血压、高发病率组盒（HMGB）-1水平和存活率。通过遥测技术连续监测结肠纵向肌肉的张力。通过颈动脉导管监测动脉血压。 TAK-242 通过颈静脉导管静脉内给药。将豚鼠分为对照组，给予载体（安慰剂乳剂），实验组在给予10 mg/kg脂多糖（LPS）前1小时给予3或10 mg/kg TAK-242。在对照组中，结肠纵向肌张力以时间依赖性方式下降，血压降低，在给予LPS后1-3小时观察到最大效果。在TAK-242治疗组中，LPS诱导的肠松弛和低血压被显着抑制。在对照组中，LPS 给药后 HMGB-1 水平升高，而该反应在 TAK-242 治疗组中被显着阻断。重要的是，TAK-242治疗后存活率增加。 总之，本研究的结果表明，TAK-242抑制脓毒症豚鼠模型中与内毒素血症相关的症状，因此它可能是脓毒症的有效治疗方法。
TAK-242 is a novel compound that suppresses nitric oxide and cytokine production by selectively inhibiting intracellular signals from toll-like receptor (TLR)-4. In the present study, we investigated the effectiveness of TAK-242 against sepsis using an endotoxaemia model in conscious and unrestricted guinea-pigs. Measures examined included muscle tension paralysis of the intestine, blood pressure, high morbidity group box (HMGB)-1 levels and survival rate.Tension of the longitudinal muscle of the colon was monitored continuously by telemetry. Arterial blood pressure was monitored via a carotid artery catheter. TAK-242 was administered intravenously through a jugular vein catheter. Guinea-pigs were divided into a control group, given vehicle (placebo emulsion), and the experimental group, administered 3 or 10 mg/kg TAK-242, 1 h before administration of 10 mg/kg lipopolysaccharide (LPS).In the control group, the tension of the longitudinal muscle of the colon decreased in a time-dependent manner and blood pressure was reduced, with maximal effects observed 1-3 h after administration of LPS. In the TAK-242-treated group, LPS-induced relaxation of the intestine and hypotension were significantly inhibited. In the control group, HMGB-1 levels were increased after LPS administration and this reaction was significantly blocked in the TAK-242-treated group. Importantly, survival rate was increased after TAK-242 treatment.In conlusion, the results of the present study show that TAK-242 inhibited the symptoms associated with endotoxaemia in a guinea-pig model of sepsis and that it may, therefore, be an effective treatment for sepsis.