Edaravone, a novel free radical scavenger, prevents liver injury and mortality in rats administered endotoxin.
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.
Kono
Hiroshi
H
First Department of Surgery, University of Yamanashi, Tamaho, Nakakoma, Japan. hkouno@res.yamanashi-med.ac.jp
Asakawa
Masami
M
Fujii
Hideki
H
Maki
Akira
A
Amemiya
Hidetake
H
Yamamoto
Masayuki
M
Matsuda
Masanori
M
Matsumoto
Yoshiro
Y
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
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