Modulation of acute and chronic inflammatory processes by cacospongionolide B, a novel inhibitor of human synovial phospholipase A2.
1. Cacospongionolide B is a novel marine metabolite isolated from the sponge Fasciospongia cavernosa. In in vitro studies, this compound inhibited phospholipase A2 (PLA2), showing selectivity for secretory PLA2 (sPLA2) versus cytosolic PLA2 (cPLA2), and its potency on the human synovial enzyme (group II) was similar to that of manoalide. 2. This activity was confirmed in vivo in the 8 h zymosan-injected rat air pouch, on the secretory enzyme accumulating in the pouch exudate. Cacospongionolide B, that is bioavailable when is given orally, reduced the elevated levels of sPLA2 present in paw homogenates of rats with adjuvant arthritis. 3. This marine metabolite showed topical anti-inflammatory activity on the mouse ear oedema induced by 12-O-tetradecanoylphorbol acetate (TPA) and decreased carrageenin paw oedema in mice after oral administration of 5, 10 or 20 mg kg(-1). 4. In the mouse air pouch injected with zymosan, cacospongionolide B administered into the pouch, induced a dose-dependent reduction in the levels of eicosanoids and tumour necrosis factor alpha (TNFalpha) in the exudates 4 h after the stimulus. It also had a weak effect on cell migration. 5. The inflammatory response of adjuvant arthritis was reduced by cacospongionolide B, which did not significantly affect eicosanoid levels in serum, paw or stomach homogenates and did not induce toxic effects. 6 Cacospongionolide B is a new inhibitor of sPLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation. This marine metabolite was active after oral administration and able to modify TNFalpha levels, and may offer an interesting approach in the search for new anti-inflammatory agents.
Departamento de Farmacología, Universidad de Valencia, Facultad de Farmacia, Spain.
P
P
García Pastor
S
S
De Rosa
A
A
De Giulio
M
M
Payá
M J
MJ
Alcaraz
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000208:Acute Disease; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004798:Enzymes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013582:Synovial Fluid / Q000201:enzymology; D020298:U937 Cells
D000890:Anti-Infective Agents; D004798:Enzymes; D011714:Pyrans; C098384:cacospongionolide B; D010741:Phospholipases A; D054467:Phospholipases A2; D015107:4-Butyrolactone