Protective effect of chloral hydrate against lipopolysaccharide/D-galactosamine-induced acute lethal liver injury and zymosan-induced peritonitis in mice.

In recent years, certain anesthetics have been shown to have protective effects against acute inflammation in experimental animals, an observation that may yield new options for adjunctive treatment of acute inflammation. In this study, we investigated the effects of chloral hydrate (CH) on the acute inflammatory response in BALB/c mice using lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced acute lethal liver injury and zymosan A-induced peritonitis models. The survival of mice following LPS/D-GalN treatment was significantly improved by a single injection with chloral hydrate, which could be administered simultaneously or as late as 3h after challenge with LPS/D-GalN; liver injury was also attenuated. A sharp rise in serum levels of MCP-1, IL-6 and TNF-alpha was attenuated or delayed after chloral hydrate treatment. Furthermore, the mechanism by which chlorate hydrate inhibits inflammation was associated with an attenuated increase in nuclear factor kappaappaB (NF-kappaB) activity in NF-kappaB-RE-luc mice upon LPS/D-GalN treatment. In mice with acute peritonitis, leukocyte number and protein concentration in peritoneal exudates peaked with a 16h lag, and serum levels of MCP-1, IL-6 and TNF-alpha were significantly lower at certain time points in the chloral hydrate-treated group compared to those in the normal saline (NS)-treated control group. In addition, chloral hydrate treatment in vitro attenuated the upregulation of TNF-alpha and IL-6 by peritoneal macrophages and NF-kappaB activity in RAW264.7 cells stimulated with LPS, suggesting that monocytes/macrophages may be a target of chloral hydrate. These results indicate that chloral hydrate has a protective effect against LPS/D-GalN-induced acute lethal liver injury in mice, which may be associated with an inhibition of NF-kappaB activity and delays in proinflammatory cytokine production. However, this phenomenon was not associated with levels of serum corticosterone. Chloral hydrate also attenuated the inflammatory response in zymosan A-induced acute peritonitis, a model of mild inflammation. In conclusion, treatment with only a single injection of chloral hydrate could significantly attenuate acute inflammation in mice treated with LPS/D-GalN and zymosan A. These effects are also likely associated with the inhibition of NF-kappaB activity.