Modulation of acute and chronic inflammatory processes by cacospongionolide B, a novel inhibitor of human synovial phospholipase A2

Abstract

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.

Figure 1

Chemical structure of cacospongionolide B.

Figure 2

Activity of human synovial sPLA₂ as a function of enzyme concentration in the absence or presence of cacospongionolide B. Data are the means±s.e.mean of n=6. Different enzyme concentrations were preincubated with vehicle (control) or cacospongionolide B (1 μM) for 5 min at 37°C, and after addition of substrate, incubation proceeded for 15 min.

Figure 3

Effect of cacospongionolide B (CB) and indomethacin (I) on mouse paw oedema induced by carrageenin. Data represent means±s.e.mean of n=6. ^*P<0.05; ^**P<0.01, significantly different from control (C). Cacospongionolide B (5–20 mg kg⁻¹) and indomethacin (10 mg kg⁻¹) were administered p.o. 1 h before the injection of carrageenin.

Figure 4

Effect of cacospongionolide B on the mouse air pouch injected with zymosan. Data represent means±s.e.mean of n=6. ^*P<0.05; ^**P<0.01 with respect to the zymosan control group. Cacospongionolide B was injected into the air pouch at the same time as zymosan. S=saline, Z=zymosan. (a) Number of cells present in exudates 4 h after zymosan. (b) PGE₂ levels in exudates. (c) LTB₄ levels in exudates. (d) TNFα levels in exudates.

Figure 5

Effect of cacospongionolide B (20 mg kg⁻¹) p.o. and indomethacin (5 mg kg⁻¹) p.o. on the development of adjuvant-induced arthritis in female Lewis rats. Values are the means ±s.e.mean of n=6. ^*P<0.05; ^**P<0.01 with respect to the vehicle-treated arthritic rats.