Kono Hiroshi, Asakawa Masami, Fujii Hideki, Maki Akira, Amemiya Hidetake, Yamamoto Masayuki, Matsuda Masanori, Matsumoto Yoshiro
First Department of Surgery, University of Yamanashi, Tamaho, Nakakoma, Japan.
J Pharmacol Exp Ther. 2003 Oct;307(1):74-82. doi: 10.1124/jpet.103.053595. Epub 2003 Sep 3.
We postulated that a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone; EDA), would attenuate inflammatory cytokine and chemokine expression in the liver after lipopolysaccharide (LPS) challenge through its antioxidant effect. Rats were administered EDA (0.3, 1.5, 3.0, 6.0, and 12.0 mg/kg) or the same volume of saline intravenously just after LPS (10 mg/kg) injection and then was continued intermittently every 2 h (five administrations in total). Survival was assessed for the next 24 h. In separate experiments, rats were sacrificed at 60 min, 90 min, 6 h, and 9 h after LPS injection. Serum and liver sections were collected for further analysis. Survival was improved by EDA in a dose-dependent manner up to 3 mg/kg, and maximum effects were observed at a dose of 3 mg/kg. After LPS injection, alanine aminotransferase levels increased significantly to about 1,250 IU/l in the vehicle-treated group, whereas values were blunted by about 80% by EDA. Furthermore, increases in 4-hydroxynonenal-modified proteins were also blunted in the liver by EDA. Moreover, mRNA expressions of macrophage infiltrating protein-2, monocyte chemoattractant protein (MCP)-1 and MCP-5 were attenuated by EDA. As a result, increases in the number of infiltrating inflammatory cells and mRNA expression of inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 were significantly blunted in the liver by EDA. This reduction was accompanied by a significant reduction of their serum levels. In conclusion, EDA prevented liver injury by both inhibition of recruitments of inflammatory cells and expression of inflammatory cytokine levels in the liver.
我们推测，一种新型自由基清除剂3-甲基-1-苯基-2-吡唑啉-5-酮（依达拉奉；EDA），通过其抗氧化作用，可减轻脂多糖（LPS）攻击后肝脏中炎性细胞因子和趋化因子的表达。大鼠在注射LPS（10mg/kg）后立即静脉注射EDA（0.3、1.5、3.0、6.0和12.0mg/kg）或相同体积的生理盐水，然后每2小时间歇给药一次（共给药五次）。接下来的24小时评估生存率。在单独的实验中，在LPS注射后60分钟、90分钟、6小时和9小时处死大鼠。收集血清和肝脏切片进行进一步分析。EDA以剂量依赖方式提高生存率，直至3mg/kg，在3mg/kg剂量时观察到最大效果。注射LPS后，载体处理组的丙氨酸转氨酶水平显著升高至约1250IU/L，而EDA使其值降低约80%。此外，EDA还使肝脏中4-羟基壬烯醛修饰蛋白的增加受到抑制。此外，EDA使巨噬细胞浸润蛋白-2、单核细胞趋化蛋白（MCP）-1和MCP-5的mRNA表达减弱。结果，EDA使肝脏中浸润性炎性细胞数量的增加以及肿瘤坏死因子-α和白细胞介素-6等炎性细胞因子的mRNA表达显著减弱。这种减少伴随着它们血清水平的显著降低。总之，EDA通过抑制炎性细胞的募集和肝脏中炎性细胞因子水平的表达来预防肝损伤。
