Immunopharmacology and InflammationAnti-inflammatory and analgesic activity of a novel inhibitor of microsomal prostaglandin E synthase-1 expression
Introduction
Among the prostaglandins, PGE2 exists in a wide variety of cells and tissues and it plays an important role in different physiological functions (Serhan and Levy, 2003). In addition, PGE2 is one of the major mediators of inflammation and its production in inflammation sites coincides with the upregulation of cyclooxygenase-2 (COX-2) expression in activated cells. COX-2 has been targeted for the treatment of various inflammatory disorders by using nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids, which inhibit the expression of a great number of proinflammatory proteins (Mitchell and Warner, 1999). Prostaglandin E synthase (PGES) enzymes are involved in the biosynthesis of PGE2 that acts down-stream of COX (Jakobsson et al., 1999a, Murakami et al., 2000). Among them, the microsomal and membrane-bound prostaglandin E synthase (namely mPGES-1) has received much more attention and has established itself as a novel drug target in the areas of inflammation (Mancini et al., 2001, Claveau et al., 2003, Kojima et al., 2005), tumorigenesis, and bone disorders being involved in a number of diseases including arthritis (Fahmi, 2004, Westman et al., 2004), atherosclerosis (Wang et al., 2006), stroke (Murakami et al., 2003, Cheng et al., 2006) and cancer (Cohen et al., 2003, Golijanin et al., 2004). This inducible enzyme is an attractive target for drug development, as inhibition would specifically diminish the PGE2 production associated with clinical disorders while preserving the production of other prostaglandins. The availability of pharmacologically active molecules capable of selective inhibition of PGE2 synthesis may provide information about this therapeutic approach that would exhibit anti-inflammatory and analgesic efficacy (Samuelsson et al., 2007, Friesen and Mancini, 2008).
We have recently reported the synthesis of a first collection of analogues bearing aromatic portions on the γ-hydroxybutenolide scaffold, showing that a 4-benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one derivative (BTH) (Fig. 1) is an inhibitor of prostanoid production through the selective modulation of microsomal prostaglandin E synthase 1 expression (mPGES-1) (Guerrero et al., 2007).
The purpose of the present study was to investigate the in vivo effect of this compound on acute and chronic inflammatory models (mouse air pouch and collagen-induced arthritis, respectively) as well as on an acute hyperalgesic model (acetic acid writhing reaction) in order to evaluate the anti-inflammatory and analgesic profile which has been associated to the mPGES-1 pharmacological modulation. We have postulated that the mPGES-1 inhibitor expression profile of this compound could provide a potential therapeutic agent as well as a pharmacological tool to discern the role of this inducible enzyme in inflammatory disorders.
Section snippets
Reagents
BTH was synthesized following known procedures recently published (Guerrero et al., 2007). [5,6,8,9,11,12,14,15(n)3H]LTB4 was from Perkin Elmer (Boston, MA). [5,6,8,11,12,14,15(n)-3H]PGE2, [5,6,8,11,12,14,15(n)-3H]Thromboxane B2 and the enhanced chemiluminescence system were from Amersham Biosciences (Barcelona, Spain). COX-2 and mPGES-1 polyclonal antisera as well as 6-keto Prostaglandin F1α EIA kit were purchased from Cayman Chemical Co. (Ann Arbor, MI). The peroxidase-conjugated goat
Effect on mouse air pouch
In the present work, we selected the 24 h zymosan-injected mouse air pouch model of inflammation on the basis of previous studies indicating the time course of leukocyte infiltration and inflammatory mediator production in this model (Posadas et al., 2000). Intrapouch administration of BTH exhibited a significative and dose-dependent inhibition of PGE2 production (Fig. 2C) and mPGES-1 protein expression (Fig. 2E) in pouch exudates. In contrast, 6-keto PGF1α levels determined as the stable
Discussion
There is unequivocal evidence that mPGES-1 plays a pivotal role in the production of PGE2 linked to inflammatory processes. A number of preclinical in vivo models of inflammation, pain and fever have been studied, and the induction of mPGES-1 has been implicated in the pathological development of these experimental models (Samuelsson et al., 2007, Claveau et al., 2003, Guay et al., 2004).
We have recently described the synthesis and pharmacological profile of BTH, a novel inhibitor of mPGES-1
Acknowledgements
MD Guerrero was the recipient of a Research Fellowship from FPU program (AP 20041633) of Spanish Ministerio de Educación y Ciencia. This work was supported in part by Grant FIS PI051659 from Spanish Instituto de Salud Carlos III. The authors are grateful to Aitana Braza-Boïls (Department of Pharmacology, University of Valencia) for the technical assistance to obtain the tissue sections.
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