title: Edaravone, a novel free radical scavenger, prevents liver injury and mortality in rats administered endotoxin.
abstract: 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.
authors.affiliation: First Department of Surgery, University of Yamanashi, Tamaho, Nakakoma, Japan. hkouno@res.yamanashi-med.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kono
authors.forename: Masami
authors.initials: M
authors.lastname: Asakawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Akira
authors.initials: A
authors.lastname: Maki
authors.forename: Hidetake
authors.initials: H
authors.lastname: Amemiya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsuda
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Matsumoto
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D054407:Chemokine CCL4; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D019742:Chemokines, CC; D019743:Chemokines, CXC; D004195:Disease Models, Animal; D000077553:Edaravone; D019446:Endotoxemia / Q000473:pathology / Q000517:prevention & control; D004731:Endotoxins / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D019410:Interleukin-16 / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood; D007962:Leukocytes / Q000502:physiology; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C108814:CCL15 protein, human; D054407:Chemokine CCL4; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D004731:Endotoxins; D016166:Free Radical Scavengers; D036341:Intercellular Signaling Peptides and Proteins; D019410:Interleukin-16; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D000410:Alanine Transaminase; D000077553:Edaravone; D000983:Antipyrine