Inhibition of microsomal prostaglandin E₂ synthase‐1 as a molecular basis for the anti‐inflammatory actions of boswellic acids from frankincense

Abstract

BACKGROUND AND PURPOSEFrankincense, the gum resin derived from Boswellia species, showed anti-inflammatory efficacy in animal models and in pilot clinical studies. Boswellic acids (BAs) are assumed to be responsible for these effects but their anti-inflammatory efficacy in vivo and their molecular modes of action are incompletely understood. EXPERIMENTAL APPROACHA protein fishing approach using immobilized BA and surface plasmon resonance (SPR) spectroscopy were used to reveal microsomal prostaglandin E2 synthase-1 (mPGES1) as a BA-interacting protein. Cell-free and cell-based assays were applied to confirm the functional interference of BAs with mPGES1. Carrageenan-induced mouse paw oedema and rat pleurisy models were utilized to demonstrate the efficacy of defined BAs in vivo. KEY RESULTSHuman mPGES1 from A549 cells or in vitro-translated human enzyme selectively bound to BA affinity matrices and SPR spectroscopy confirmed these interactions. BAs reversibly suppressed the transformation of prostaglandin (PG)H2 to PGE2 mediated by mPGES1 (IC50 = 3-10 mM). Also, in intact A549 cells, BAs selectively inhibited PGE2 generation and, in human whole blood, b-BA reduced lipopolysaccharide-induced PGE2 biosynthesis without affecting formation of the COX-derived metabolites 6-keto PGF1a and thromboxane B2. Intraperitoneal or oral administration of b-BA (1 mg·kg -1 ) suppressed rat pleurisy, accompanied by impaired levels of PGE2 and b-BA (1 mg·kg -1 , given i.p.) also reduced mouse paw oedema, both induced by carrageenan. CONCLUSIONS AND IMPLICATIONSSuppression of PGE2 formation by BAs via interference with mPGES1 contribute to the anti-inflammatory effectiveness of BAs and of frankincense, and may constitute a biochemical basis for their anti-inflammatory properties.

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…mPGES-1 as target of these NPs may provide a basis for their antiinflammatory properties and rationalize their use in folk medicine as remedy for treatment of inflammatory disorders. Among these plant-derived mPGES-1 inhibitors are prominent antiinflammatory and anti-tumoral compounds like the polyphenol curcumin from turmeric [86], epigallocatechin-3-gallate (EGCG) from green tea [87], the acylphloroglucinol hyperforin from St. John´s wort [66] and garcinol from Garcinia indica [88], triterpene acids from frankincense (e.g., tirucallic acids, lupeolic acids, boswellic acids,) [89,90], the diterpenoids carnosol and carnosic acid from Salvia officinalis [91], and the quinone embelin from Embelia ribes [92]. All of them inhibit mPGES-1 in cell-free assays in the submicromolar range (Table 1).…”

Survey on the Quality of the Top-Selling European and American Botanical Dietary Supplements Containing Boswellic Acids

“…1). Whereas in the past the anti-inflammatory effects were mainly attributed to the inhibition of 5-LO by AKBA [11], recent research revealed the relevance of the whole fraction of triterpenoid acids and the involvement of much more molecular targets than only 5-LO, especially catG and mPGES-1 [9,[12][13][14][15]. Commercially available frankincense consists of the oleo gum resin obtained from trees of Boswellia serrata Roxb.…”

Development and optimization of boswellic acid-loaded proniosomal gel

“…Earlier studies have suggested that both KBA and AKBA interfere with production of leukotrienes by inhibition 5-lipoxygenase; however, more recent research has shown that other BAs specially b-boswellic acid also play an important role, targeting the microsomal prostaglandin (PG) E2 synthase-1 (mPGES-1) as well as cathepsin G (CatG) thereby complementing the inflammatory action of KBA and AKBA (Tausch et al, 2009;Abdel et al, 2011;Siemoneit et al, 2011;Skarke et al, 2012).…”