A novel mPGES-1 inhibitor alleviates inflammatory responses by downregulating PGE2 in experimental models

Publication date: Available online 20 June 2019Source: Prostaglandins & Other Lipid MediatorsAuthor(s): Hwi-Ho Lee, YoonHyoung Moon, Ji-Sun Shin, Jeong-Hun Lee, Tae-Woo Kim, Changyoung Jang, Changmin Park, Juhee Lee, Younghoon Kim, Younggwan Kim, Oliver Werz, Boyoung Y. Park, Jae Yeol Lee, Kyung-Tae LeeAbstractWe previously reported the strong inhibitory potency of N-phenyl-N’-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) 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 PGE2 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 (PGI2) and thromboxane A2 (TXA2). Our data suggest that PBCH downregulates PGE2 production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.Graphical abstract
Source: Prostaglandins and Other Lipid Mediators - Category: Lipidology Source Type: research