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As the inducible terminal enzyme for prostaglandin E2 (PGE2) synthesis, microsomal PGE synthase-1 (mPGES-1) contributes to neuroinflammation and secondary brain injury after cerebral ischemia via producing excessive PGE2. However, a proof of concept that mPGES-1 is a therapeutic target for ischemic stroke has not been established by a pharmacological strategy mainly due to the lack of drug-like mPGES-1 inhibitors that can be used in relevant rodent models. To this end, we recently developed a series of novel small-molecule compounds that can inhibit both human and rodent mPGES-1. In this study, blockade of mPGES-1 by our several novel compounds abolished the lipopolysaccharide (LPS)-induced PGE2 and pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α) in mouse primary brain microglia. Inhibition of mPGES-1 also decreased PGE2 produced by neuronal cells under oxygen–glucose deprivation (OGD) stress. Among the five enzymes for PGE2 biosynthesis, mPGES-1 was the most induced one in cerebral ischemic lesions. Systemic treatment with our lead compound MPO-0063 (5 or 10 mg/kg, i.p.) in mice after transient middle cerebral artery occlusion (MCAO) improved post-stroke well-being, decreased infarction and edema, suppressed induction of brain cytokines (IL-1β, IL-6, and TNF-α), alleviated locomotor dysfunction and anxiety-like behavior, and reduced the long-term cognitive impairments. The therapeutic effects of MPO-0063 in this proof-of-concept study provide the first pharmacological evidence that mPGES-1 represents a feasible target for delayed, adjunct treatment — along with reperfusion therapies — for acute brain ischemia. [ABSTRACT FROM AUTHOR]

[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]