Edaravone, a novel free radical scavenger, prevents liver injury and mortality in rats administered endotoxin
Edaravone, a novel free radical scavenger, prevents liver injury and mortality in rats administered endotoxin
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DOI：
10.1124/jpet.103.053595
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
Matsumoto, Y
中科院分区：
文献类型：
--
作者：
Kono, H;Asakawa, M;Matsumoto, Y
我们推测，一种新的自由基清除剂，3-甲基-1-苯基-2-吡唑啉-5-酮（依达拉奉; EDA），将减弱炎症细胞因子和趋化因子在脂多糖（LPS）的挑战后，通过其抗氧化作用在肝脏中的表达。在注射LPS（10 mg/kg）后立即静脉内给予大鼠EDA（0.3、1.5、3.0、6.0和12.0 mg/kg）或相同体积的生理盐水，然后每2 h间歇地继续（总共5次给药）。评估接下来24小时的存活率。在单独的实验中，在注射LPS后60 min、90 min、6 h和9 h处死大鼠。收集血清和肝脏切片用于进一步分析。高达3 mg/kg的剂量依赖性方式，EDA改善了存活率，并在3 mg/kg剂量下观察到最大效应。LPS注射后，赋形剂治疗组的丙氨酸氨基转移酶水平显著增加至约1，250 IU/l，而EDA使该值减弱约80%。此外，4-羟基壬烯醛修饰的蛋白质的增加也被EDA钝化。EDA可抑制巨噬细胞浸润蛋白-2、单核细胞趋化蛋白-1和单核细胞趋化蛋白-5的mRNA表达。结果，EDA显著减弱了肝脏中浸润炎性细胞数量和炎性细胞因子（如肿瘤坏死因子-α和白细胞介素-6）mRNA表达的增加。这种降低伴随着其血清水平的显著降低。总之，EDA通过抑制肝脏中炎性细胞的募集和炎性细胞因子水平的表达来防止肝损伤。
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.