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, and Lee, Jae Yeol
[Display omitted] • The genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE 2 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. 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 PGE 2 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 (PGE 2 IC 50 = 41.77 nM; mPGES-1 IC 50 = 1.16 nM) exhibited a potent neuroprotection (ED 50 = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC 50 = >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. [ABSTRACT FROM AUTHOR]