INHIBITION OF INFLAMMATORY RESPONSES BY A SERIES OF NOVEL DOLABRANE DERIVATIVES

Four dolabrane derivatives isolated from Endospermum diadenum have bee n studied for their inhibitory effects on murine models of inflammatio n and human neutrophil functions in vitro. After topical application, akendo 1, akendo 2 and akendo 3 potently inhibited the mouse ear oedem a induced by 12-O-tetradecanoylphorbol acetate (TPA) with a striking e ffect on myeloperoxidase levels. After oral administration, akendo 2 a nd akendo 3 inhibited mouse paw oedema induced by carrageenan, with a significant reduction in myeloperoxidase levels. In contrast to indome thacin, they did not modify the prostaglandin E(2) content of the infl ammed paw. None of the compounds affected superoxide generation by hum an neutrophils. On the contrary, they inhibited degranulation induced by different stimuli. The most effective compounds were akendo 2 and a kendo 3, which also inhibited myeloperoxidase activity. All compounds were weak inhibitors of leukotriene B-4 synthesis and release by human neutrophils, whereas only akendo 3 decreased 5-lipoxygenase activity. Cyclo-oxygenase-1 from human platelets was inhibited mainly by akendo 2 and akendo 3, although with a low potency. The latter compound also reduced weakly the synthesis of prostaglandin E(2) by cyclo-oxygenase -2. The anti-inflammatory activity of these dolabrane derivatives was not related to arachidonic acid mobilization or metabolism.