Hepatoprotective effect and mechanistic insights of deoxyelephantopin,a phyto-sesquiterpene lactone,against fulminant hepatitis

Deoxyelephantopin (DET) is an abundant sesquiterpene lactone isolated from an anecdotally hepatoprotective phytomedicine, Elephantopus scaber. Our objective in this study was to provide scientific evidence for the in vivo efficacy and the underlying mechanisms of action of DET in lipopolysaccharide/d-galactosamine (LPS/D-GalN)-induced fulminant hepatitis. We investigated both the protective effect of pretreatment with DET (10 mg/kg body weight, Pre-DET10) prior to administration of LPS/D-GalN and the therapeutic effect of treatment with 10 mg/kg DET (Post-DET10) or the hepatoprotective drug silymarin (Post-SM10) following the administration of LPS/D-GalN. Our data showed that Pre-DET10 prevented LPS/D-GalN-induced infiltration of F4/80 monocytes/macrophages and an increase of nitrotyrosine and cyclooxygenase-2 protein in liver tissues. Further, Post-DET10 and Psot-SM10 treatments protected against liver cell apoptosis. All three treatments suppressed serum aminotransferase activities, tumor necrosis factor-alpha and interleukin-6 levels, and serum and hepatic matrix metalloproteinase-9 activity. The Pre-DET10 or Post-DET10 and Post-SM10 treatments in combination with inhibition of heme oxygenase-1 expression ultimately decreased protection of mice from LPS/D-GalN-induced mortality, with decreased survival from 75% and 62.5% to 50%, respectively. Results obtained from serial liver scintigraphy with ^99mTc-diisopropyl iminodiacetic acid (DISIDA) on single-photon emission computed tomography analysis showed that both liver uptake and excretion times of DISIDA were significantly delayed in LPS/D-GalN-treated animals and were effectively recovered by DET and silymarin treatment. This report demonstrates that DET functions in the modulating multiple molecular targets or signaling pathways that counteract inflammation during the progression of fulminant hepatitis and may serve as a novel lead compound for future development of anti-inflammatory or hepatoprotective agents.