Vol. 289, Issue 1, 166-172, April 1999

Effects of Petrosaspongiolide M, a Novel Phospholipase A₂ Inhibitor, on Acute and Chronic Inflammation¹

Pablo Garcia-Pastor, Antonio Randazzo, Luigi Gomez-Paloma, M. Jose Alcaraz and Miguel Paya

Departamento de Farmacología, Universidad de Valencia, Facultad de Farmacia, Valencia, Spain (P.G.-P., M.J.A., M.P.); and Dipartimento di Chimica delle Sostanze Naturali, Universitá degli Studi di Napoli "Federico II," Napoli, Italy (A.R., L.G.-P.)

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- 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 PGE₂ levels 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.