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Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A₄

Robert B. Zurier^*,1, Yee-Ping Sun, Kerri L. George^*, Judith A. Stebulis^*, Ronald G. Rossetti^*, Ann Skulas^*, Erica Judge^* and Charles N. Serhan

^* University of Massachusetts Medical School, Division of Rheumatology, Worcester, Massachusetts, USA; and

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

¹ Correspondence: University of Massachusetts Medical School, Division of Rheumatology, 55 Lake Ave, Worcester, MA 01655, USA. E-mail: robert.zurier{at}umassmed.edu

Ajulemic acid (AjA), a synthetic nonpsychoactive cannabinoid, and lipoxin A₄ (LXA₄), an eicosanoid formed from sequential actions of 5- and 15-lipoxygenases (LOX), facilitate resolution of inflammation. The purpose of this study was to determine whether the ability of AjA to limit the progress of inflammation might relate to an increase in LXA₄, a known anti-inflammatory and proresolving mediator. Addition of AjA (0–30 µM) in vitro to human blood and synovial cells increased production of LXA₄ (ELISA) 2- to 5-fold. Administration of AjA to mice with peritonitis resulted in a 25–75% reduction of cells invading the peritoneum, and a 7-fold increase in LXA₄ identified by mass spectrometry. Blockade of 12/15 LOX, which leads to LXA₄ synthesis via 15-HETE production, reduced (>90%) the ability of AjA to enhance production of LXA₄ in vitro. These results suggest that AjA and other agents that increase endogenous compounds that facilitate resolution of inflammation may be useful for conditions characterized by inflammation and tissue injury.—Zurier, R. B., Sun, Y.-P., George, K. L., Stebulis, J. A., Rossetti, R. G., Skulas, A., Judge, E., Serhan, C. N. Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A₄.

Key Words: lipoxygenase • resolution • arthritis • nephritis