Preliminary studies on phospholipase A2‐induced mouse paw edema as a model to evaluate antiinflammatory agents

Abstract

Phospholipase A₂ (PLA₂) is a key component of the inflammatory process because of its role in the generation of eicosanoids and platelet‐activating factor (PAF). Manipulation of PLA₂ activity offers a novel therapeutic approach for the development of antiinflammatory agents; however, there is a need for a suitable in vivo model. Injection of 1 μg of snake venom PLA₂ (A. piscivorus piscivorus, D‐49) into the mouse hind footpad produced a significant three‐ to four‐fold rise in paw edema within 10 min, compared to the saline control. Edema formation depended on enzyme concentration and appeared specific for PLA₂ since edema was negated by enzyme pretreatment with p‐bromophenacyl bromide, a nonspecific PLA₂ inhibitor. Moreover, injection of a protein such as bovine serum albumin did not result in significant edema. Coinjection of phenidone (lipoxygenase inhibitor, 50 μg), indomethacin (cyclooxygenase inhibitor, 50 μg), cyproheptadine (antihistamine/antiserotonin, 50 μg), aristolochic acid (putative PLA₂ inhibitor, 100 μg), or kadsurenone (PAF antagonist, 50μg) with PLA₂ (1 μg/paw) resulted in partial reduction (44.5, 34.2, 54.7, 64, and 50% inhibition, respectively) of edema formation. Oral administration of cyproheptadine (10 mg/kg), indomethacin (10 mg/kg), BW 755c (100 mg/kg), or dexamethasone (1 mg/kg) 1–3 h before challenge also decreased PLA₂‐induced edema (63.0, 30.1, 47.8, or 62.5% inhibition, respectively). The data suggest that mouse paw edema resulting from PLA₂ injection is a multicomponent event, influenced by both autacoids and lipid mediators of inflammation.