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.
Footnotes
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Send reprint requests to: Dr. M. Payá, Departamento de Farmacologı́a, Universidad de Valencia, Facultad de Farmacia, Avda. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain. E-mail Miguel.paya{at}uv.es
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↵1 This work was supported by Grant SAF98–0119 from Comisión Interministeñal de Ciencia y Tecnología, Spanish Ministerio de Educación y Ciencia.
- Abbreviations:
- PLA2
- phospholipase A2
- sPLA2
- secretory phospholipase A2
- cPLA2
- cytosolic phospholipase A2
- COX-1
- cyclooxygenase-1
- COX-2
- cyclooxygenase-2
- 5-LO
- 5-lipoxygenase
- LPS
- lipopolysaccharide
- LT
- leukotriene
- iNOS
- inducible nitric oxide synthase
- NSAID
- nonsteroidal anti-inflammatory drug
- PG
- prostaglandin
- TNF-α
- tumor necrosis factor-α
- TXB2
- thromboxane B2
- Received August 25, 1998.
- Accepted November 3, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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