Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells

Aims: To better understand mechanisms whereby Ajulemic acid (AjA), a synthetic antiinflammatory cannabinoid, promotes resolution of acute and chronic inflammation in animal models, we investigated its influence on cyclooxygenase 2 (COX2) expression and eicosanoid production in human fibroblast-like synovial cells (FLS). Main methods: FLS isolated from tissue obtained at joint replacement surgery or cultured from synovial fluid were treated for 60 min with AjA (10-30 mu M), then stimulated with tumor necrosis factor alpha (TNF alpha). COX2 mRNA was measured by hybridization/colorimetric assay of whole cell lysates collected 4 h after Stimulation. To determine FLS were incubated with C-14-arachidonic acid for 20 h then treated with AjA (8-effects on arachidonic acid release, 32 mu M). Arachidonic acid release was measured by scintillation counting. Prostaglandins (PC) were measured by enzyme linked immunosorbent assay (ELISA) in cell supernatants collected 4 and 24 h after stimulation. Key findings: AjA increased the steady state levels of COX2 mRNA in and arachidonic acid release from FLS. Treatment of FLS with AjA increased 15-deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)) production in a concentration dependent manner, but did not affect PGE(2) production significantly. Significance: The capacity of AjA to increase selectively and markedly 15d-PGJ2, all eicosanoid which facilitates resolution of inflammation, suggests that AjA may have value as a therapeutic agent for the treatment of rheumatoid arthritis (RA) and other diseases characterized by acute and chronic inflammation. (C) 2008 Elsevier Inc. All rights reserved.