Parthenolide is a
sesquiterpene lactone used in
folk medicine for its anti-inflammatory activity. Recent in vitro studies have shown that this compound inhibits the nuclear factor (
NF)-kappaB pathway. This study examines the effect of
parthenolide in endotoxic
shock in rodents. Endotoxic
shock was induced by administration of
Escherichia coli endotoxin in rats. Three groups of rats received
parthenolide (0.25, 0.5, or 1 mg/kg) 15 min before
endotoxin; another group received
parthenolide (1 mg/kg) 3 h after
endotoxin. In vehicle-treated rats, administration of
endotoxin caused severe
hypotension, which was associated with a marked hyporeactivity to
norepinephrine in ex vivo thoracic aortas. Immunohistochemistry showed positive staining for
nitrotyrosine,
poly(ADP-ribose)
synthetase (PARS) and apoptosis, whereas Northern blot analysis showed increased
mRNA expression of
inducible nitric-oxide synthase (iNOS) in thoracic aortas. Elevated levels of plasma
nitrate/
nitrite were also found. Elevated lung levels of
myeloperoxidase activity were indicative of infiltration of neutrophils. These inflammatory events were preceded by cytosolic degradation of inhibitor kappaBalpha (
IkappaBalpha) and activation of nuclear
NF-kappaB in the lung. In vivo pretreatment and post-treatment with
parthenolide improved the hemodynamic profile and reduced plasma
nitrate/
nitrite and lung neutrophil infiltration in a dose-dependent fashion. Vascular hyporeactivity of ex vivo aortas was ameliorated. Treatment with
parthenolide also abolished
nitrotyrosine formation, PARS expression, and apoptosis and reduced iNOS
mRNA content in thoracic aortas.
DNA binding of
NF-kappaB was inhibited by
parthenolide in the lung, whereas degradation of
IkappaBalpha was unchanged. In a separate set of experiments, pretreatment or post-treatment with
parthenolide significantly improved survival in mice challenged with
endotoxin. We conclude that
parthenolide exerts beneficial effects during endotoxic
shock through inhibition of
NF-kappaB.