Parthenolide, an Inhibitor of the Nuclear Factor-κB Pathway, Ameliorates Cardiovascular Derangement and Outcome in Endotoxic Shock in Rodents

孤雌内酯 硝基酪氨酸 一氧化氮 药理学 免疫印迹 体内 αBκ 一氧化氮合酶 白屈菜红碱 亚硝酸盐 细胞凋亡 NF-κB 化学 生物 内分泌学 生物化学 信号转导 硝酸盐 蛋白激酶C 生物技术 有机化学 基因
作者
Maeve Sheehan,Hector R. Wong,Paul W. Hake,Vivek Malhotra,Michael O’Connor,Basilia Zingarelli
出处
期刊:Molecular Pharmacology [American Society for Pharmacology and Experimental Therapeutics]
卷期号:61 (5): 953-963 被引量:110
标识
DOI:10.1124/mol.61.5.953
摘要

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)-κB 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 κBα (IκBα) and activation of nuclear NF-κB 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-κB was inhibited by parthenolide in the lung, whereas degradation of IκBα 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-κB.
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