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

Ajulemic acid (AjA), a synthetic nonpsychoactive cannabinoid, and lipoxin A(4) (LXA(4)), 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 LXA(4), a known anti-inflammatory and proresolving mediator. Addition of AjA (0-30 microM) in vitro to human blood and synovial cells increased production of LXA(4) (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 LXA(4) identified by mass spectrometry. Blockade of 12/15 LOX, which leads to LXA(4) synthesis via 15-HETE production, reduced (>90%) the ability of AjA to enhance production of LXA(4) 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.

Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid.

Interleukin-6 (IL-6) is a multifunctional cytokine which contributes to inflammation and tissue injury in several diseases. Thus, inhibition of IL-6 production may be a useful strategy for treatment of patients with diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A synthetic nonpsychoactive cannabinoid, ajulemic acid (AjA), prevents joint damage in experimental arthritis. Results of experiments presented here indicate that addition of AjA (3-30 microM) to human monocyte derived macrophages in vitro reduces steady state levels of IL-6 mRNA and the subsequent secretion of IL-6 from LPS stimulated cells. Although AjA binds to and activates PPARgamma, its anti IL-6 effects are PPARgamma independent. These studies provide evidence to support the view that AjA may prove to be an effective, safe antiinflammatory agent.