Preliminary studies on phospholipase A2-induced mouse paw edema as a model to evaluate antiinflammatory agents.
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 microgram 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 micrograms), indomethacin (cyclooxygenase inhibitor, 50 micrograms), cyproheptadine (antihistamine/antiserotonin, 50 micrograms), aristolochic acid (putative PLA2 inhibitor, 100 micrograms), or kadsurenone (PAF antagonist, 50 micrograms) with PLA2 (1 microgram/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.
Marshall
L A
LA
Immunopharmacology Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Chang
J Y
JY
Calhoun
W
W
Yu
J
J
Carlson
R P
RP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D005528:Foot; D051379:Mice; D010740:Phospholipases / Q000633:toxicity*; D010741:Phospholipases A / Q000633:toxicity*; D054467:Phospholipases A2
D000893:Anti-Inflammatory Agents; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2