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.