Abstract

The marine product petrosaspongiolide M is a novel inhibitor of phospholipase A₂ (PLA₂), showing selectivity for secretory PLA₂ versus cytosolic PLA₂, with a potency on the human synovial enzyme (group II) similar to that of manoalide. This compound was more potent than manoalide on bee venom PLA₂ (group III) and had no effect on group I enzymes (Naja naja and porcine pancreatic PLA₂). Inhibition of PLA₂ was also observed in vivo in the zymosan-injected rat air pouch, on the secretory enzyme accumulated in the pouch exudate. Petrosaspongiolide M decreased carrageenan paw edema in mice after the oral administration of 5, 10, or 20 mg/kg. This marine metabolite (0.01–1.0 μmol/pouch) induced a dose-dependent reduction in the levels of prostaglandin (PG)E₂, leukotriene B₄, and tumor necrosis factor-α in the mouse air pouch injected with zymosan 4 h after the stimulus. It also had a weaker effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by petrosaspongiolide M, which also inhibited leukotriene B₄ levels in serum and PGE₂ levels in paw homogenates. In contrast with indomethacin, this marine compound did not reduce PGE₂levels in stomach homogenates. Petrosaspongiolide M is a new inhibitor of secretory PLA₂ in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation.