Influence of OAS-1000 on mediators of inflammation

OAS-1000 is a semisynthetic derivative of pseudopterosine A, isolated from sea whip (Pseudopterogorgia elizabethae), that has been shown to have topical anti-inflammatory activity. The purpose of this research was to investigate OAS-1000 for potential use as an anti-inflammatory agent for topical oral application, and to begin to investigate a mechanism of action. OAS-1000 was therefore evaluated as an inhibitor of 4 enzymes of the arachidonic acid metabolic pathways (prostaglandin G/H synthase I (PGHS-1, COX-1), prostaglandin G/H synthase II (PGHS-2, COX-2), arachidonate 5-lipoxygenase (5-LOX), and arachidonate 15-lipoxygenase (15-LOX)). It was found that OAS-1000 inhibits PGHS-1 activity with an IC-50 value of 80.3 microM, but had much less activity versus PGHS-2 enzyme and no activity versus the 15-LOX enzyme. 5-LOX activity showed some inhibition, but only at a high OAS-1000 concentrations. Additionally, OAS-1000 was tested for it's ability inhibit 1 ng/ml IL-1beta stimulated PGE2 production in a cell culture system. Inhibition of 46% was seen at an OAS-1000 concentration of 22.4 microM. Taken together, these experiments suggest that at least some of the topical anti-inflammatory activity of OAS-1000 may be attributed to inhibition of the arachidonic acid metabolites that have been shown to be important in inflammation and tissue destruction.