[Manoalide: a new phospholipase A2 inhibitor of marine origin with potential immunoregulatory effect]

Manoalide, a non-steroidal sesterterpenoid isolated from a marine sponge, is a potent analgesic and antiinflammatory compound. Manoalide inhibits phospholipase A2 from extracellular sources (snake venoms, bee, etc.), the release of arachidonic acid from rabbit polymorphonuclear leukocytes as well as calcium mobilization. This suggests that the anti-inflamatory effect might be caused by the regulation of eicosanoid biosynthesis. The macrophage plays a major role in the immune response and the inflammatory process, it has the capacity to synthesize and secrete arachidonic acid oxygenation products derived from both cyclooxygenase and lipoxygenase catalyzed pathways, and has been used extensively to study the effect of inhibitors of phospholipases, cyclooxygenase and lipoxygenase enzymes. Our results demonstrate that Manoalide modified the release of arachidonic acid and its further metabolism into prostaglandins and leukotrienes in mouse cultured peritoneal macrophages stimulated by phorbol myristate acetate, calcium ionophore A23187 and zymosan. Since eicosanoids have been shown to cause pain, we studied the possibility that the analgesic effect of Manoalide might be correlated with a decrease of eicosanoid release in vivo. The fact that Manoalide reduced both zymosan-induced peritoneal writhing in the mouse and the synthesis of both 6-keto-prostaglandin F1 alfa and leukotriene C4 suggests that the analgesic effect of Manoalide is at least in part linked to the inhibition of eicosanoid production in vivo. Since it has been shown that eicosanoids have immunoregulatory functions, a future possibility is that a phospholipase A2 inhibitor such as Manoalide may prove useful to investigate the biological role of eicosanoid metabolites on the immune function.