A novel mPGES-1 inhibitor alleviates inflammatory responses by downregulating PGE2 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-2 (PGE(2)) 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(2) 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 prosfaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI(2)) and thromboxane A(2) (TXA(2)). Our data suggest that PBCH downregulates PGE(2) production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.