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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Edaravone, a Novel Free Radical Scavenger, Prevents Liver Injury and Mortality in Rats Administered Endotoxin

First Department of Surgery, University of Yamanashi, Yamanashi, Japan (H.K., M.A., A.M., H.A., M.M., Y.M.); and Department of Surgery, Shinko Byoin Hospital, Hyogo, Japan (M.Y.)

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- 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.

Address correspondence to: Dr. Hiroshi Kono, First Department of Surgery, University of Yamanashi, 1110 Shimokato, Tamaho, Nakakoma, Yamanashi 409-3898, Japan. E-mail: hkouno{at}res.yamanashi-med.ac.jp

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