Suppression of lethal toxicity of endotoxin by biscoclaurine alkaloid cepharanthin.
Suppressive effects of Cepharanthin (CE) on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) production followed by liver injury were investigated. Pretreatment with CE reduced limulus activity of LPS. Intraperitoneal treatment with CE 10 min before an i.v. challenge of LPS resulted in protection from LPS lethality in D-galactosamine (GalN)-sensitized BALB/c but not in C57BL/6 and C57BL/10ScSn mice. Treatment with CE before the LPS challenge significantly reduced serum TNF levels in a dose-dependent manner. The suppression was most effective when CE was administered 10 min before the LPS challenge. Increased levels of enzymes released from hepatocytes into the circulation, as a result of LPS-induced liver injury, were reduced by CE administration. Histological evaluation demonstrated that massive cell infiltration after severe injury developed in liver of mice injected with LPS plus D-GalN unless they were pretreated with CE. Apoptotic cells decreased by treatment with CE. Treatment with CE retarded lethal shock induced by an infection with 10(8) CFU Salmonella typhimurium deltaaroA mutant. These results suggest that action of CE is initiated through suppression of LPS-induced TNF production.
Maruyama
H
H
Department of Pathology, School of Allied Health Sciences, School of Pharmaceutical Sciences, Kitasato University, Sagamihara, Japan.
Kikuchi
S
S
Kawaguchi
K
K
Hasunuma
R
R
Ono
M
M
Ohbu
M
M
Kumazawa
Y
Y
D000410:Alanine Transaminase / Q000097:blood; D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000097:blood; D044182:Benzylisoquinolines; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000097:blood; D005260:Female; D005688:Galactosamine / Q000494:pharmacology; D008033:Limulus Test; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012481:Salmonella Infections, Animal / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D012486:Salmonella typhimurium / Q000472:pathogenicity; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects; D052117:Benzodioxoles
D000410:Alanine Transaminase; D000470:Alkaloids; D001219:Aspartate Aminotransferases; D001427:Bacterial Toxins; D044182:Benzylisoquinolines; D004731:Endotoxins; D005688:Galactosamine; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C027952:salmonella toxin; C006947:cepharanthine; D052117:Benzodioxoles