Variabilin: A Dual Inhibitor of Human Secretory and Cytosolic Phospholipase A2 With Anti-inflammatory Activity

The marine product variabilin was identified as a novel inhibitor of phospholipase A2 (PLA2), which exhibited IC50 values of 6.9 μM and 7.9 μM for human synovial secretory PLA2 and U937 cells cytosolic PLA2activities, respectively. This compound was less potent on bee venom or zymosan-injected rat air pouch enzymes and failed to affect Naja naja venom PLA2. The production of leukotriene B4 by human neutrophils stimulated with calcium ionophore A23187 was also inhibited by variabilin, which was without effect on 5-lipoxygenase, cyclo-oxygenase 1 and cyclo-oxygenase 2 activities in cell-free assays. Other functions of human neutrophils, such as degranulation and superoxide generation, were also significantly reduced in vitro . Variabilin administered topically suppressed the mouse ear edema induced by 12- O -tetradecanoylphorbol 13-acetate, whereas the ear edema induced by arachidonic acid was unaffected; this suggests an action previous to arachidonic acid metabolism. This compound administered p.o. at 30 mg/kg and 45 mg/kg significantly inhibited mouse paw edema induced by carrageenan and, at 0.01 to 1.0 μmol/pouch in the mouse air pouch injected with zymosan, exerted a marked inhibition on PGE2 and leukotriene B4 levels in exudates (ID50 values of approximately 0.028–0.029 μmol/pouch), without affecting cell migration. Our results indicate that variabilin is an inhibitor of human secretory and cytosolic PLA2activities that controls eicosanoid production in vitro and in vivo , inhibits neutrophil degranulation and superoxide generation in vitro and shows anti-inflammatory activity after topical or p.o. administration to mice.