Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase A2 with anti-inflammatory activity.

The flavanonylflavone morelloflavone inhibited secretory phospholipase A2 (PLA2) in vitro, with a high potency on the human recombinant synovial and bee venom enzymes (IC50 = 0.9 and 0.6 microM, respectively). The inhibition was apparently irreversible. In contrast, the compound was inactive on cytosolic PLA2 activity from human monocytes. Morelloflavone scavenged reactive oxygen species generated by human neutrophils (IC50 = 2.7 and 1.8 microM for luminol and lucigenin, respectively) but did not modify cellular responses such as degranulation or eicosanoid release. This biflavonoid exerted anti-inflammatory effects in animal models, with a potent inhibition of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear inflammation in mice after topical administration. In this test, morelloflavone was found to decrease oedema and myeloperoxidase levels in ear homogenates ID50 = 58.5 and 74.3 micrograms/ear, respectively). In contrast, this biflavonoid failed to modify arachidonic acid-induced ear inflammation or eicosanoid levels in ear homogenates. A significant anti-inflammatory effect was also observed in the mouse paw carrageenan edema after oral administration, with the highest inhibition at 3 hr after induction of inflammation. Morelloflavone is an inhibitor of secretory PLA2 with selectivity for groups II and III enzymes and may be a pharmacological tool. In addition, it shows anti-inflammatory activity apparently not related to the synthesis of eicosanoids, but likely dependent on other mechanisms such as scavenging of reactive oxygen species.