Eicosanoids derived from arachidonic acid, mainly prostaglandins (PGs) and leukotrienes (LTs) function as powerful lipid mediators in inflammatory reactions. The dual inhibition of the LT-producing enzyme 5-lipoxygenase (5-LO) and of microsomal PGE2 synthase-1 (mPGES-1, which forms pro-inflammatory PGE2 from COX-2 derived PGH2), is a novel and promising strategy for the therapy of inflammation. The acylphloroglucinol arzanol has recently been suggested as an active ingredient responsible for the anti-inflammatory effects of the plant Helichrysum italicum. Here we analysed the effect of arzanol on LT and PGE2 formation in cell-free and cell-based models as well as in an experimental model of inflammation in rats. We find that arzanol inhibits 5-LO and mPGES-1 (IC50=5µM and 0.5µM, respectively) in cell-free assays and efficiently reduces mPGES-1-derived PGE2 formation in LPS-stimulated human monocytes (at 3µM) and LPS-stimulated human whole blood (at 10µM) with a similar efficiency as the specific mPGES-1 inhibitor MD-52 (tested at 2 and 5µM). In human neutrophils arzanol inhibited 5-LO product formation with an IC50=5µM. The in vivo efficiency of arzanol (3.6mg/kg i.p.) was demonstrated by the reduction of exudate volume (59%), number of inflammatory cells (48%) and PGE2 (47%) and LTB4 (31%) levels, in the pleural exudates of rats in a model of carrageenan-induced pleurisy. Taken together arzanol is a potent inhibitor of 5-LO and mPGES-1 in both cell-free and cell-based assays with significant anti-inflammatory effects in vivo.
