Protective effects of antimicrobial peptides derived from the beetle Allomyrina dichotoma defensin on endotoxic shock in mice.
Synthetic peptides, Arg-Leu-Tyr-Leu-Arg-Ile-Gly-Arg-Arg-NH2 (peptide A) and Arg-Leu-Arg-Leu-Arg-Ile-Gly-Arg-Arg-NH2 (peptide B), derived from the beetle Allomyrina dichotoma defensin, have not only antimicrobial activities but also anti-inflammatory effects by inhibiting tumour necrosis factor-alpha(TNF-alpha) production. In the present study, we evaluated the lipopolysaccharide (LPS)-binding activities and the protective effects of these peptides on LPS-induced lethal shock in d-galactosamine (GalN)-sensitized mice. These peptides were shown to bind to erythrocytes coated with LPS and the binding activity of peptide A to LPS was significantly higher than those of peptide B and polymyxin B. Mice were injected intraperitoneally with peptide A or B at doses of 25, 50, 100 and 150 mg/kg before an injection of Salmonella abortusequi LPS (5 microg/kg) and GalN (1 g/kg) (LPS+GalN). All of wild-type mice died within 24 h after challenged with LPS+GalN. All of TNF-alpha-deficient mice challenged with LPS+GalN survived. An injection of peptide A immediately after challenge with LPS+GalN resulted in significantly improved survival rates in a dose dependent manner. Peptide B showed only minor protection. The levels of TNF-alpha in the ameliorated mice by peptide A were significantly lower than those of challenge control, suggesting a suppressive effect of peptide A on TNF-alpha production. Furthermore, peptide A-treated mice showed significantly lower levels of asparate aminotransferase and alanine aminotransferase when compared to challenge control. Concordantly, hemorrhage and necrosis in the liver of peptide A-treated mice were less apparent than those of untreated control mice. These results suggest that peptide A has a protective effect on LPS-induced mortality in this mouse model.
Koyama
Yukari
Y
Department of Epidemiology, National Institute of Animal Health, Tsukuba, Ibaraki, Japan.
Motobu
Maki
M
Hikosaka
Kenji
K
Yamada
Manabu
M
Nakamura
Kikuyasu
K
Saido-Sakanaka
Hisako
H
Asaoka
Ai
A
Yamakawa
Minoru
M
Sekikawa
Kenji
K
Kitani
Hiroshi
H
Shimura
Kameo
K
Nakai
Yutaka
Y
Hirota
Yoshikazu
Y
D000371:Agglutination; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use*; D001517:Coleoptera / Q000737:chemistry*; D023082:Defensins / Q000737:chemistry / Q000627:therapeutic use*; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005688:Galactosamine / Q000494:pharmacology; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced; D007668:Kidney / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D012475:Salmonella / Q000737:chemistry; D012772:Shock, Septic / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D023082:Defensins; D008070:Lipopolysaccharides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine