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Protective effects of isohelenin, an inhibitor of nuclear factor B, in endotoxic shock in rats

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

H.R. Wong

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

P.W. Hake

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

B. Zingarelli

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

Recent in vitro studies have shown that isohelenin, a sesquiterpene lactone, inhibits the NF-B pathway. This study examines the effect of isoheleninin endotoxic shock induced by administration of Escherichia coli endotoxinin male Wistar rats. A group of rats received isohelenin (2 mg/kg intraperitoneally)15 min before endotoxin. In vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to norepinephrine and acetylcholine in ex vivo aortas. Elevated levels of plasma nitrate/nitrite, metabolites of nitric oxide (NO), were also found. These inflammatory events were preceded by cytosolic degradation of inhibitor-B (IB) and activation of nuclear factor-B (NF-B) in the lung within 15 min of endotoxin administration. Treatment with isohelenin resulted in hemodynamicimprovement and reduced plasma levels of NO metabolites. Nuclear translocation of NF-B was inhibited by isohelenin treatment in the lung, whereas degradation of IB was unchanged. In a separate set of experiments, treatment with isohelenin significantly improved survival in mice challenged with endotoxin. We conclude that isohelenin exerts beneficial therapeutic effects during endotoxic shock through inhibition of NF-B.

Journal of Endotoxin Research, Vol. 8, No. 2, 99-107 (2002)
DOI: 10.1177/09680519020080020301


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