Mayer A M, Glaser K B, Jacobs R S
Department of Biological Sciences, University of California, Santa Barbara.
J Pharmacol Exp Ther. 1988 Mar;244(3):871-8.
The marine natural produce manoalide has been reported to inactivate venom phospholipase A2 from several sources and phospholipase A2 from polymorphonuclear leukocytes. In this investigation, the regulation of eicosanoid production was studied both in an in vitro and in an in vivo model. The release of arachidonic acid and prostaglandin E2 was inhibited by manoalide when cultured mouse peritoneal macrophages were stimulated with phorbol myristate acetate (apparent IC50 = 0.23 microM), calcium ionophore A23187 (apparent IC50 = 0.23 microM) and zymosan (apparent IC50 = 0.18 microM). Leukotriene C4 production was inhibited by manoalide when macrophages were stimulated by A23187 (IC50 = 0.35 microM) but was enhanced when the cells were stimulated with zymosan. In an in vivo model, manoalide antagonized zymosan-induced peritoneal writhing in the mouse (ED50 = 0.71 mg/kg) and inhibited the i.p. release of 6-keto-prostaglandin F1 alpha (ED50 = 0.2 mg/kg) and leukotriene C4 (ED50 = 0.24 mg/kg). Our results suggest that: 1) manoalide modifies arachidonic acid release and metabolism to prostaglandins and leukotrienes in mouse cultured peritoneal macrophages stimulated by phorbol myristate acetate, calcium ionophore A23187 and zymosan and 2) the analgesic properties of manoalide seem to be partially correlated with reduced eicosanoid production in zymosan-stimulated mouse peritoneal exudates.
据报道，海洋天然产物 manoalide 可使多种来源的毒液磷脂酶 A2 和多形核白细胞的磷脂酶 A2 失活。在本研究中，我们在体外和体内模型中研究了类花生酸生成的调节。当用佛波酯肉豆蔻酸酯（表观 IC50 = 0.23 μM）、钙离子载体 A23187（表观 IC50 = 0.23 μM）和酵母聚糖（表观 IC50 = 0.18 μM）刺激培养的小鼠腹腔巨噬细胞时，花生四烯酸和前列腺素 E2 的释放受到 manoalide 的抑制。当巨噬细胞受到 A23187 刺激时，白三烯 C4 的生成受到 manoalide 的抑制（IC50 = 0.35 μM），但当细胞受到酵母聚糖刺激时，白三烯 C4 的生成则增强。在体内模型中，manoalide 拮抗酵母聚糖诱导的小鼠腹腔扭体反应（ED50 = 0.71 mg/kg），并抑制腹腔注射 6-酮-前列腺素 F1α（ED50 = 0.2 mg/kg）和白三烯 C4（ED50 = 0.24 mg/kg）的释放。我们的结果表明：1）manoalide 改变了由佛波酯肉豆蔻酸酯、钙离子载体 A23187 和酵母聚糖刺激的小鼠培养腹腔巨噬细胞中花生四烯酸的释放以及向前列腺素和白三烯的代谢；2）manoalide 的镇痛特性似乎与酵母聚糖刺激的小鼠腹腔渗出液中类花生酸生成的减少部分相关。
