ABSTRACT-This study was performed to establish a useful method for monitoring the effects of in hibitors of 5-lipoxygenase (5-LO) and/or cyclooxygenase (CO) and for differential evaluation of these in hibitors. After oral dosing, CO inhibitors such as indomethacin (20-40 mg/kg) and ketoprofen (40-80 mg/kg), zileuton (5-LO inhibitor, 20 80 mg/kg) and MK886 (5-LO-activating-protein inhibitor, 640 mg/kg) potently suppressed arachidonic acid (AA, 0.25 mg)-induced ear edema in mice. Methysergide (serotonin antagonist, 20 mg/kg) showed a slight anti-edematous effect, while mepyramine (160 mg/kg) and bromelain (320 mg/kg) had no effect. The anti-edematous effects of indomethacin and ketoprofen were reduced by concomitant topical application of prostaglandin E2 (PGE2, 1 ug/ear), but not by concomitant intradermal application of leukotriene C4 (LTC4, 0.1 pg/ear). On the contrary, the anti-edematous effects of zileuton and MK886 were reduced by LTC4, but not by PGE2. Dual (5-LO and CO) inhibitors such as phenidone (80-160 mg/kg) and BW755C (40 80 mg/kg), which inhibited the biosynthesis of LTB4 13 -15 times more potently than that of PGE2 in rat peritoneal exudate cells, also showed anti-edematous effects that were reduced by LTC4, but not by PGE2. These results suggest that the AA (0.25 mg)-induced ear edema in mice is mainly mediated by LTs and PGs and is suitable for evaluating inhibitors of 5-LO and/or CO, and that an application of LTC4 or PGE2 with AA is a useful method for differential evaluation of these inhibitors.
Keywords:Arachidonic acid-induced ear edema, Prostaglandin E2, Leukotriene C4, Indomethacin, ZileutonIt is well established that prostaglandins (PGs), cyclo oxygenase (CO) products of arachidonic acid (AA), are involved in inflammatory reactions as important inflam matory mediators, and inhibitors of PG biosynthesis have been developed as non-steroidal anti-inflammatory drugs. Recently, it has been shown that leukotrienes (LTs), 5 lipoxygenase (5-LO) products of AA, are also involved in inflammatory reactions as proinflammatory mediators. LTC4 and LTD4 cause edema together with increased microvascular permeability (1, 2), and LTB4 causes leuko cyte chemotaxis (3, 4). These findings have prompted in terest in developing dual inhibitors of 5-LO and CO as anti-inflammatory drugs.Several experimental models of inflammation such as carrageenan-induced paw edema and AA-induced ear ede ma have been widely used for the discovery and evalu ation of anti-inflammatory drugs. The carrageenan-in duced paw edema in rats is known to be sensitive to CO in hibitors, but not to 5-LO inhibitors (5, 6). On the other hand, the AA-induced ear edema in mice is known to be suitable for evaluating 5-LO inhibitors (7 -10), but the effects of CO inhibitors on ear edema are not consistent. It has been demonstrated that indomethacin, piroxicam and naproxen suppressed AA-induced ear edema (7, 9, 10), while aspirin, ibuprofen and naproxen failed to suppress it (8, 10). Griswold et al. (10) showed that the suppressive effect of indo...
