Arzanol; a prenylated heterodimeric phloroglucinyl pyrone; inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy

Julia Bauer (1) , Andreas Koeberle (1) , Friederike Dehm (1, 2) , Federica Pollastro (3) , Giovanni Appendino (3) , Hinnak Northoff (4) , Antonietta Rossi (2) , Lidia Sautebin (2) , Oliver Werz (3)

1 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
2 Department of Experimental Pharmacology
3 Dipartimento di Scienze Chimiche
4 University Medical Center

Based on its capacity to inhibit HIV-1 replication in T cells and the release of pro-inflammatory cytokines in monocytes, the prenylated heterodimeric phloroglucinyl α-pyrone arzanol was identified as the major anti-inflammatory and antiviral constituent from . We have now investigated the activity of arzanol on the biosynthesis of pro-inflammatory eicosanoids, evaluating its anti-inflammatory efficacy and . Arzanol inhibited 5-lipoxygenase (EC 7.13.11.34) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC 1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E (IC=2.3 - 9μM). Detailed studies revealed that arzanol primarily inhibits microsomal PGE synthase (mPGES)-1 (EC 5.3.99.3, IC=0.4μM) rather than COX-2. In fact, arzanol could block COX-2/mPGES-1-mediated PGE biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, but not the concomitant COX-2-derived biosynthesis of thromboxane B or of 6-keto PGF, and the expression of COX-2 or mPGES-1 protein was not affected. Arzanol potently suppressed the inflammatory response of the carrageenan-induced pleurisy in rats (3.6mg/kg, i.p.), with significantly reduced levels of PGE in the pleural exudates. Taken together, our data show that arzanol potently inhibits the biosynthesis of pro-inflammatory lipid mediators like PGE and , providing a mechanistic rationale for the anti-inflammatory activity of , and a rationale for further pre-clinical evaluation of this novel anti-inflammatory lead.

Mots clés: 5-lipoxygenase; leukotriene; prostaglandin; inflammation; phloroglucinol

Julia Bauer, Andreas Koeberle, Friederike Dehm, Federica Pollastro, Giovanni Appendino, et al.. Arzanol; a prenylated heterodimeric phloroglucinyl pyrone; inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy. Biochemical Pharmacology, 2010, 81 (2), pp.259. ⟨10.1016/j.bcp.2010.09.025⟩. ⟨hal-00649889⟩