1. Academic Validation
  2. Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation

Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation

  • Prostaglandins Other Lipid Mediat. 2013 Dec:107:26-34. doi: 10.1016/j.prostaglandins.2013.09.001.
Patrick Leclerc 1 Helena Idborg Linda Spahiu Charlotte Larsson Natalia Nekhotiaeva Johan Wannberg Patric Stenberg Marina Korotkova Per-Johan Jakobsson
Affiliations

Affiliation

  • 1 Department of Medicine, Rheumatology Research Unit, Karolinska Institutet, S-171 77 Stockholm, Sweden. Electronic address: Patrick.Leclerc@ki.se.
Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III) and studied its impact on the prostanoid profile in various models of inflammation. Compound III is a benzoimidazole, which has a submicromolar IC50 in both human and rat recombinant mPGES-1. In cellular assays, it reduced PGE2 production in A549 cells, mouse macrophages and blood, causing a shunt to the prostacyclin pathway in the former two systems. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE2 production and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE2 production and tended to decrease the levels of other prostanoids.

Keywords

Air pouch model; Inflammation; Macrophages; Mouse; PGE2; mPGES-1.

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