ABSTRACT
Bacterial endotoxin produces sepsis associated with alterations in body temperature (fever or hypothermia). The intraperitoneal administration of bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/mouse) led to a decrease in colonic temperature starting 1 hr after the injection. The hypothermic effect was accompanied by a significant increase in hypothalamic leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) levels. 5-lipoxygenase inhibitor, zileuton (200 and 400 mg/kg, po) administered 30 min before LPS challenge significantly prevented hypothermia. However, non-selective cyclooxygenase inhibitor, indomethacin (10, 20 mg/kg, po) did not reverse the hypothermic response. Further, pretreatment of mice with zileuton prevented LPS-stimulated increase in hypothalamic LTB4 levels and caused a relatively small increase in PGE2 levels. Indomethacin had no effect on LTB4 levels but it reduced PGE2 levels. These results suggest a possible involvement of leukotrienes in LPS-induced hypothermia and the potential protective role of 5-lipoxygenase inhibitors in endotoxemia.
Subject(s)
Animals , Arachidonate 5-Lipoxygenase/antagonists & inhibitors , Colon/drug effects , Dinoprostone/metabolism , Female , Hydroxyurea/analogs & derivatives , Hypothalamus/drug effects , Hypothermia/drug therapy , Hypothermia, Induced , Indomethacin/pharmacology , Leukotriene B4/metabolism , Leukotrienes/physiology , Lipopolysaccharides/pharmacology , Lipoxygenase Inhibitors/pharmacology , Male , MiceABSTRACT
A novel series of N-aryl-N-hydroxyurea derivatives [III] was synthesized for possible biological activity as inhibitors of 5-lipoxygenase