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

Recent in vitro studies have shown that isohelenin, a sesquiterpene lactone, inhibits the NF-kappaB pathway. This study examines the effect of isohelenin in endotoxic shock induced by administration of Escherichia coli endotoxin in 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-kappaBalpha (IkappaBalpha) and activation of nuclear factor-kappaB (NF-kappaB) in the lung within 15 min of endotoxin administration. Treatment with isohelenin resulted in hemodynamic improvement and reduced plasma levels of NO metabolites. Nuclear translocation of NF-kappaB was inhibited by isohelenin treatment in the lung, whereas degradation of IkappaBalpha 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-kappaB.