Eugenosedin-A amelioration of lipopolysaccharide-induced up-regulation of p38 MAPK, inducible nitric oxide synthase and cyclooxygenase-2.
In this study, we investigate the protective effects of eugenosedin-A on p38 mitogen-activated protein kinase (MAPK), inflammatory nitric oxide (NO) and cyclooxygenase-2 (COX-2) pathways in a rat model of endotoxin shock. Rats were pretreated with eugenosedin-A, trazodone, yohimbine (1 mg kg(-1), i.v.), aminoguanidine or ascorbic acid (15 mg kg(-1), i.v.) 30 min before endotoxin challenge. Endotoxaemia was induced by a single i.v. injection of lipopolysaccharide (LPS, 10 mg kg(-1)). In rats not treated with eugenosedin-A, LPS increased plasma concentrations of NO and prostaglandin E(2) (PGE(2)), and levels of p38 MAPK, inducible NO synthase (iNOS) and COX-2 proteins in the liver, lung, aorta and lymphocytes. In the pre-treated rats, eugenosedin-A not only inhibited the LPS-induced NO and PGE(2) levels but also attenuated the LPS-induced increase in p38 MAPK and iNOS levels in the liver, aorta and lymphocytes. Eugenosedin-A also reduced LPS-induced COX-2 proteins in the aorta and lymphocytes. Likewise, aminoguanidine, ascorbic acid, yohimbine and trazodone were also found to decrease NO and PGE(2) concentrations after endotoxin challenge. While aminoguanidine and ascorbic acid also attenuated the LPS-induced increase in p38 MAPK, iNOS and COX-2 proteins in the aorta and lymphocytes, trazodone and yohimbine inhibited only the increase in p38 MAPK, iNOS and COX-2 proteins in lymphocytes. Finally, eugenosedin-A (10(-10)-10(-8) M) significantly inhibited the biphasic response induced by hydrogen peroxide (10(-6)-3 x 10(-5) M) in rat denudated aorta. Taken together, the results of this study indicate that eugenosedin-A, as well as ascorbic acid, can attenuate free-radical-mediated aortic contraction and relaxation. It may therefore be able to reduce the damage caused by septic shock by inhibiting formation of p38 MAPK, iNOS, COX-2 and free radicals.
Shen
Kuo-Ping
KP
Department of Early Childhood Care and Education, Meiho Institute of Technology, Pingtung, Taiwan.
Liou
Shu-Fen
SF
Hsieh
Su-Ling
SL
Chen
Ing-Jun
IJ
Wu
Bin-Nan
BN
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009928:Organ Specificity; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology; D014196:Trazodone / Q000494:pharmacology; D015854:Up-Regulation; D015016:Yohimbine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis*
D000317:Adrenergic alpha-Antagonists; D000975:Antioxidants; D006146:Guanidines; D008070:Lipopolysaccharides; D010879:Piperazines; D012702:Serotonin Antagonists; C496985:eugenosedin-A; D015016:Yohimbine; D006861:Hydrogen Peroxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid; C004479:pimagedine; D014196:Trazodone