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Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo.
FASEB J. 2013 Jun; 27(6):2328-41.FJ

Abstract

The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1β and a cell-free mPGES-1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1β-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 μM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1α, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis.

Authors+Show Affiliations

Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23447581

Citation

Kats, Anna, et al. "Inhibition of Microsomal Prostaglandin E Synthase-1 By Aminothiazoles Decreases Prostaglandin E2 Synthesis in Vitro and Ameliorates Experimental Periodontitis in Vivo." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 27, no. 6, 2013, pp. 2328-41.
Kats A, Båge T, Georgsson P, et al. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. FASEB J. 2013;27(6):2328-41.
Kats, A., Båge, T., Georgsson, P., Jönsson, J., Quezada, H. C., Gustafsson, A., Jansson, L., Lindberg, C., Näsström, K., & Yucel-Lindberg, T. (2013). Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 27(6), 2328-41. https://doi.org/10.1096/fj.12-214445
Kats A, et al. Inhibition of Microsomal Prostaglandin E Synthase-1 By Aminothiazoles Decreases Prostaglandin E2 Synthesis in Vitro and Ameliorates Experimental Periodontitis in Vivo. FASEB J. 2013;27(6):2328-41. PubMed PMID: 23447581.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. AU - Kats,Anna, AU - Båge,Tove, AU - Georgsson,Pierre, AU - Jönsson,Jörgen, AU - Quezada,Hernán Concha, AU - Gustafsson,Anders, AU - Jansson,Leif, AU - Lindberg,Claes, AU - Näsström,Karin, AU - Yucel-Lindberg,Tülay, Y1 - 2013/02/27/ PY - 2013/3/1/entrez PY - 2013/3/1/pubmed PY - 2013/8/3/medline KW - PGE2 KW - anti-inflammatory KW - cyclooxygenase-2 KW - gingival fibroblasts KW - interleukin-1β KW - mPGES-1 inhibitor SP - 2328 EP - 41 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 27 IS - 6 N2 - The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1β and a cell-free mPGES-1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1β-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 μM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1α, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/23447581/Inhibition_of_microsomal_prostaglandin_E_synthase_1_by_aminothiazoles_decreases_prostaglandin_E2_synthesis_in_vitro_and_ameliorates_experimental_periodontitis_in_vivo_ L2 - https://www.fasebj.org/doi/10.1096/fj.12-214445?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=www.ncbi.nlm.nih.gov DB - PRIME DP - Unbound Medicine ER -