A novel mPGES-1 inhibitor alleviates inflammatory responses by downregulating PGE 2 in experimental models

We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E (PGE ) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-...

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Published in:Prostaglandins & other lipid mediators 2019-10, Vol.144, p.106347
Main Authors: Lee, Hwi-Ho, Moon, YoonHyoung, Shin, Ji-Sun, Lee, Jeong-Hun, Kim, Tae-Woo, Jang, Changyoung, Park, Changmin, Lee, Juhee, Kim, Younghoon, Kim, Younggwan, Werz, Oliver, Park, Boyoung Y, Lee, Jae Yeol, Lee, Kyung-Tae
Format: Article
Language:English
Subjects:
A549 Cells
Animals
Anti-Inflammatory Agents - pharmacology
Anti-Inflammatory Agents - therapeutic use
Dinoprostone - biosynthesis
Dinoprostone - metabolism
Disease Models, Animal
Down-Regulation - drug effects
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Humans
Hydrazines - pharmacology
Hydrazines - therapeutic use
Inflammation - drug therapy
Inflammation - metabolism
Male
Mice
Prostaglandin-E Synthases - antagonists & inhibitors
Rats
Rats, Sprague-Dawley
RAW 264.7 Cells
Thiazoles - pharmacology
Thiazoles - therapeutic use
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Summary:We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E (PGE ) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor and evaluated its anti-inflammatory effects using in vivo experimental models. PBCH inhibited PGE production in various activated cells in addition to inhibiting the mPGES-1 activity. In the ear edema and paw edema rat models, PBCH significantly reduced ear thickness and paw swelling, respectively. Besides, in adjuvant-induced arthritis (AIA) rat model, PBCH decreased paw swelling, plasma rheumatoid factor (RF), and receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. Furthermore, while PBCH reduced the plasma prostaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI ) and thromboxane A (TXA ). Our data suggest that PBCH downregulates PGE production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.
ISSN:1098-8823