Suppression of lethal toxicity of endotoxin by biscoclaurine alkaloid cepharanthin

Suppressive effects of Cepharanthin (CE) on lipopolysaccharide (LPS)-induce d tumor necrosis factor alpha (TNF alpha) production followed by liver inju ry were investigated. Pretreatment with CE reduced limulus activity of LPS. Intraperitoneal treatment with CE 10 min before an i.v. challenge of LPS r esulted in protection from LPS lethality in D-galactosamine (GaIN)-sensitiz ed BALB/c but not in C57BL/6 and C57BL/10ScSn mice. Treatment with CE befor e the LPS challenge significantly reduced serum TNF levels in a dose-depend ent manner. The suppression was most effective when CE was administered 10 min before the LPS challenge. Increased levels of enzymes released from hep atocytes into the circulation, as a result of LPS-induced liver injury, wer e reduced by CE administration. Histological evaluation demonstrated that m assive cell infiltration after severe injury developed in liver of mice inj ected with LPS plus D-GalN unless they were pretreated with CE. Apoptotic c ells decreased by treatment with CE. Treatment with CE retarded lethal shoc k induced by an infection with 10(8) CFU Salmonella typhimurium Delta aroA mutant. These results suggest that action of CE is initiated through suppre ssion of LPS-induced TNF production.