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.
Sheehan
M
M
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Wong
H R
HR
Hake
P W
PW
Zingarelli
B
B
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004586:Electrophoresis; D004731:Endotoxins / Q000633:toxicity*; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D012717:Sesquiterpenes / Q000627:therapeutic use*; D012772:Shock, Septic / Q000503:physiopathology / Q000517:prevention & control*
D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D011506:Proteins; D012717:Sesquiterpenes; C103906:isohelenin; C044101:endotoxin, Escherichia coli; D000109:Acetylcholine; D009638:Norepinephrine