In vitro and in vivo evaluation of the anti-inflammatory effects of Arzanol from Helichrysum italicum

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.