Oxylipins Derived from Docosapentaenoic Acid (DPAn-6) Possess Potent Anti-inflammatory Activity (101.4)

Abstract

Background: The resolution of inflammation is an active process mediated by endogenous lipids formed by lipoxygenases and cyclo-oxygenases at the site of inflammation. Enzymatically oxygenated derivatives (oxylipins) of the omega-3 fatty acids DHA and EPA (resolvins) have potent resolution activity. Objectives: To determine if oxylipins are enzymatically synthesized from the omega-6 fatty acid DPAn-6 and whether these molecules possess pro-resolution, anti-inflammatory properties. Results: Two major metabolites, 17-hydroxy-DPAn-6 and 10,17-dihydroxy-DPAn-6, were formed from DPAn-6 following reaction with soybean 15-lipoxygenase. The identity of these metabolites was confirmed by LC/MS/MS, NMR, and UV analysis. 17-hydroxy-DPAn-6 was also formed following incubation of DPAn-6 with whole human blood. In a mouse air pouch model of acute inflammation, local administration of 100 ng (0.005 mg/kg) of either 17-hydroxy-DPAn-6 or 10,17-dihydroxy DPAn-6 resulted in 70–80% reduction in leukocyte trafficking, comparable to that observed following indomethacin (5 mg/kg ip) administration. The anti-inflammatory activity of both compounds was confirmed in a rat hind paw edema model of acute inflammation. Intravenous administration of 5 μg (~0.025 mg/ml) of either compound resulted in ~25% reduction in paw edema post carrageenan challenge. Both DPAn-6 oxylipins were also active in the hind paw model after oral administration. Conclusions: Oxylipins derived from DPAn-6 are natural compounds possessing potent anti-inflammatory activity. These compounds or analogs thereof are candidates for new drugs that act uniquely to resolve inflammation.