petrosaspongiolide-m and Edema

A standard aqueous extract of Mangifera indica L., used in Cuba as an antioxidant under the brand name of VIMANG, was tested in vivo for its anti-inflammatory activity using commonly accepted assays. M. indica extract, administered topically (0.5-2 mg per ear), reduced ear edema induced by arachidonic acid (AA) and phorbol myristate acetate (PMA, ED50 = 1.1 mg per ear) in mice. In the PMA model, M. indica extract also reduced myeloperoxidase (MPO) activity. This extract p.o. administered also inhibited tumor necrosis factor alpha (TNFalpha) serum levels in both models of inflammation (AA, ED50 = 106.1 mg kg(-1) and PMA, ED50 = 58.2 mg kg(-1)). In vitro studies were performed using the macrophage cell line RAW264.7 stimulated with pro-inflammatory stimuli (LPS-IFNgamma or the calcium ionophore A23187) to determine PGE2 or LTB4 release, respectively. The extract inhibited the induction of PGE2 with IC50 = 64.1 microg ml(-1) and LTB4 IC50 = 22.9 microg ml(-1). M. indica extract also inhibited human synovial secretory phospholipase (PL)A2 with IC 50 = 0.7 microg ml(-1). These results represent an important contribution to the elucidation of the mechanism involved in the anti-inflammatory and anti-nociceptive effects reported by the standard M. indica extract VIMANG.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Calcimycin; Cuba; Dexamethasone; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Ear, External; Edema; Eicosanoids; Indomethacin; Interferon-gamma; Leukotriene B4; Lipopolysaccharides; Macrophages; Male; Mangifera; Mice; Oleanolic Acid; Peroxidase; Phospholipases A; Phytotherapy; Plant Bark; Plant Extracts; Plant Stems; Plants, Medicinal; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Water; Xanthones

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 micromol/pouch) induced a dose-dependent reduction in the levels of prostaglandin (PG)E2, leukotriene B4, and tumor necrosis factor-alpha 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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cell Survival; Dinoprostone; Edema; Enzyme Inhibitors; Exudates and Transudates; Humans; In Vitro Techniques; Inflammation; Leukocytes; Leukotriene B4; Male; Mice; Oleanolic Acid; Phospholipases A; Phospholipases A2; Porifera; Rats; Rats, Inbred Lew; Rats, Wistar; Tumor Necrosis Factor-alpha; U937 Cells