In vitro and in vivo neuroprotective effect of novel mPGES-1 inhibitor in animal model of Parkinson's disease. (15th October 2022)

• Record Type: Journal Article
• Authors: Yang, Seyoung; Huh, Eugene; Moon, Gwang Hyun; Ahn, Junseong; Woo, Jiwon; Han, Hee-Soo; Lee, Hwi-Ho; Chung, Kyung-Sook; Lee, Kyung-Tae; Oh, Myung Sook; Lee, Jae Yeol
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 74(2022)
• Publication Date: 2022-10-15
• Subjects: Inflammation -- Prostaglandin E2 -- mPGES-1 -- Neuroprotection -- Motor impairments -- Parkinson's disease; mPGES-1 microsomal prostaglandin E synthase-1; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128920
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Compound 7s (MPO-0144 ) ameliorated motor impairments and dopaminergic neuronal damage in animal model of PD. Highlights: The genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE2 production and dopaminergic neurodegeneration. Compound 7s, a mPGES-1 inhibitor, exhibited potent neuroprotective activity against 6-OHDA-induced toxicity in PC12 cells. Compound 7s ( MPO-0144 ) as a small molecule could be a promising therapeutic agent for PD. Compound 7s ameliorated motor impairments and dopaminergic neuronal damage in animal model of PD. Abstract: mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson's disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE2 production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144 ) as a mPGES-1 inhibitor (PGE2 IC50 = 41.77 nM; mPGES-1 IC50 = 1.16 nM) exhibited a potent neuroprotection (ED50 = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC50 = >10 μM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p. ) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients.