Phorbol ester-induced dermal inflammation in mice: evaluation of inhibitors of 5-lipoxygenase and antagonists of leukotriene B4 receptor.
In the present investigation, the effects of selective inhibitors of 5-lipoxygenase (5-LO), zileuton and TZI-41127, E-6080, AA-861 and antagonists of leukotriene B4 (LTB4) receptors, SC-41930, and SC-51146 and a selective cyclooxygenase inhibitor, indomethacin, were examined in TPA-induced acute mouse dermal inflammation. Topical application of all these agents, except indomethacin, resulted in marked attenuation of TPA-induced edema and influx of neutrophils reflected in myeloperoxidase measurements. Topically applied SC-41930 attenuated TPA-induced edema and neutrophil influx in a dose-related manner. Oral administration of LTB4 receptor antagonists either as a pre-treatment or post-treatment attenuated TPA-induced edema and influx of neutrophils. The O-demethyl analog of SC-41930, SC-37920, which was nearly 1000-fold less active than SC-41930 in LTB4 receptor binding assays, was inactive in inflammation assays, suggesting a role for LTB4 in this response. Zileuton and TZI-41127 were more effective as anti-inflammatory agents following oral administration than after i.p. administration. Intraperitoneally administered indomethacin attenuated edema response but not influx of neutrophils. Taken together, these results suggest a role for leukotrienes in acute inflammation induced by TPA and possible utility of this model to test in vivo 5-LO inhibitors and LTB4 receptor antagonists.
Rao
T S
TS
Searle Research & Development, c/o Monsanto Co., St. Louis, MO 63198.
Yu
S S
SS
Djuric
S W
SW
Isakson
P C
PC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001578:Benzopyrans; D016859:Lipoxygenase Inhibitors; D018102:Receptors, Leukotriene B4; C059950:SC 41930; C082206:7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin