Sesquiterpene lactone parthenolide, an inhibitor of IkappaB kinase complex and nuclear factor-kappaB, exerts beneficial effects in myocardial reperfusion injury.
Sesquiterpene lactones are extracts of common medicinal Asteracae plants used in folk medicine for their anti-inflammatory activity. Recently, in vitro studies have shown that these compounds may interfere with pro-inflammatory gene regulation. This study examines the effects of parthenolide, a sesquiterpene lactone, in experimental myocardial ischemia and reperfusion. Myocardial injury was induced in rats by 30 min occlusion and 120 min reperfusion of the left coronary artery. Parthenolide (250 or 500 microg/kg) or vehicle (0.05% Tween 80, 1 mL/kg) was administered intraperitoneally 10 min before reperfusion. In vehicle-treated rats, ischemia and reperfusion caused myocardial injury, as evaluated by infarct size, serum levels of creatine phosphokinase and by histological examination. Elevated tissue levels of myeloperoxidase activity were indicative of a significant infiltration of neutrophils. This event paralleled the occurrence of oxidative damage, as evaluated by a marked increase in tissue malondialdehyde levels. These inflammatory events were preceded by activation of the IkappaB kinase complex (IKK) and partial disappearance of inhibitor-kappaBalpha (IkappaBalpha) in the cytosol and translocation of the nuclear factor-kappaB (NF-kappaB) to the nucleus, as early as 15 min after reperfusion. Administration of parthenolide ameliorated myocardial injury, lowered serum creatine phosphokinase activity, and reduced neutrophil infiltration and the subsequent oxidative damage. These beneficial effects were associated with inhibition of IKK activity, enhanced stability of IkappaBalpha, and inhibition of nuclear translocation of NF-kappaB. The results of this study suggest that parthenolide may be beneficial for the treatment of reperfusion-induced myocardial damage by inhibition of the IKK/NF-kappaB pathway.
Zingarelli
Basilia
B
Children's Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio 45229, USA.
Hake
Paul W
PW
Denenberg
Alvin
A
Wong
Hector R
HR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006439:Hemodynamics; D020672:I-kappa B Proteins; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020556:Neutrophil Infiltration / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D012717:Sesquiterpenes; D000072000:NF-KappaB Inhibitor alpha; C002669:parthenolide