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

Lee, Hwi-Ho; Moon, YoonHyoung; Shin, Ji‐Sun; Lee, Jeonghun; Kim, Taewoo; Jang, Chang-Young; Park, Changmin; Kim, Young-Hoon; Kim, Younggwan; Werz, Oliver; Park, Boyoung Y.; Lee, Jae Yeol; Lee, Kyung‐Tae

doi:10.1016/j.prostaglandins.2019.106347

Cited by 13 publications

(10 citation statements)

References 51 publications

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“…1 D). Compound PBCH, when given at a relatively high concentration (10 µM) contrasting its nanomolar potencies [ 17 , 18 , 30 ], only had negligible effects on COX enzymatic activities in an assay where non-selective COX inhibitor indomethacin and selective COX-2 inhibitor celecoxib showed substantial inhibition as positive controls (Fig. 1 E).…”

Section: Resultsmentioning

confidence: 99%

“…#AG310) was purchased from Sigma-Aldrich. Compound PBCH was kindly provided by Dr. Jae Yeol Lee [ 17 , 18 ] and authenticated using LC/MS and NMR in the Medicinal Chemistry Core at the University of Tennessee Health Science Center.…”

Section: Methodsmentioning

confidence: 99%

“…This is likely because most current mPGES-1 inhibitors are developed for the human ortholog and do not block the rodent mPGES-1 due to the interspecies difference in the enzyme structures [ 16 ]. Utilizing a recently reported selective small-molecule inhibitor of mPGES-1, N -phenyl- N' -(4-benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH), which is potent and can effectively inhibit both human and rodent orthologs [ 17 , 18 ], we herein aim to determine the feasibility of pharmacologically targeting mPGES-1 in wildtype mice following pilocarpine-induced SE. Our results demonstrate the feasibility of mPGES-1 as a promising pharmacological target for delayed adjunctive treatment that could reduce neuropathogenesis triggered by SE.…”

Section: Introductionmentioning

confidence: 99%

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Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

Yasmen

Sluter

et al. 2023

Mol Brain

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Status epilepticus (SE) in humans is characterized by prolonged convulsive seizures that are generalized and often difficult to control. The current antiseizure drugs (ASDs) aim to stop seizures quickly enough to prevent the SE-induced brain inflammation, injury, and long-term sequelae. However, sole reliance on acute therapies is imprudent because prompt treatment may not always be possible under certain circumstances. The pathophysiological mechanisms underlying the devastating consequences of SE are presumably associated with neuroinflammatory reactions, where prostaglandin E2 (PGE2) plays a pivotal role. As the terminal synthase for pathogenic PGE2, the microsomal prostaglandin E synthase-1 (mPGES-1) is rapidly and robustly induced by prolonged seizures. Congenital deletion of mPGES-1 in mice is neuroprotective and blunts gliosis following chemoconvulsant seizures, suggesting the feasibility of mPGES-1 as a potential antiepileptic target. Herein, we investigated the effects of a dual species mPGES-1 inhibitor in a mouse pilocarpine model of SE. Treatment with the mPGES-1 inhibitor in mice after SE that was terminated by diazepam, a fast-acting benzodiazepine, time-dependently abolished the SE-induced PGE2 within the brain. Its negligible effects on cyclooxygenases, the enzymes responsible for the initial step of PGE2 biosynthesis, validated its specificity to mPGES-1. Post-SE inhibition of mPGES-1 also blunted proinflammatory cytokines and reactive gliosis in the hippocampus and broadly prevented neuronal damage in a number of brain areas. Thus, pharmacological inhibition of mPGES-1 by small-molecule inhibitors might provide an adjunctive strategy that can be implemented hours after SE, together with first-line ASDs, to reduce SE-provoked brain inflammation and injury.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

Yasmen

Sluter

et al. 2023

Mol Brain

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“…mPGES-1 is induced in the delayed phase of inflammation, which is involved in wakefulness, inflammation, hyperalgesia, pain, fever, and cancer [ 14 ]. Currently, traditional NSAIDs inhibiting both COX-1 and COX-2 activities are widely used in the treatment of rheumatoid arthritis, osteoarthritis, and inflammatory pain [ 15 ]. However, COX-1 inhibition has side effects on the gastrointestinal (GI) tract and selective COX-2 inhibitors can lead to thrombosis and cardiovascular side effects by reducing vasorelaxation [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Off-Label Use of Crisdesalazine (GedaCure) in Meningoencephalitis in Two Dogs

Lee

Song

Kim

et al. 2023

Veterinary Sciences

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An 8-year-old, castrated male Shih-tzu dog (Case 1) showing ataxia and gait disorder was referred for neurological examination and magnetic resonance imaging. Through comprehensive examinations, the patient was tentatively diagnosed with meningoencephalitis of unknown origin (MUO) and treatment with prednisolone and cytosine arabinoside was started. The symptoms were improving with immunosuppressive treatment. However, severe bacterial cystitis occurred and we could not avoid tapering off prednisolone. Then, neurological signs recurred. Therefore, we added crisdesalazine, which allowed us to reduce the daily dosage of immunosuppressants easily. In another case, a 4-year-old, spayed female Yorkshire terrier dog (Case 2) was referred to our hospital showing a head tilt, circling, and loss of the menace reflex. The patient was tentatively diagnosed with MUO and treatment with some immunosuppressants was attempted. The clinical symptoms improved, but the alleviation was inadequate. Thus, we added crisdesalazine. The neurological signs then markedly improved. Moreover, the drugs could be tapered off more easily than before. Crisdesalazine is a novel drug that has antioxidant and anti-inflammatory action in brain disease and is used particularly for dementia. In this paper, we tried an off-label use of this drug in canine MUO patients, and found that it had, in these two patients, additional therapeutic effects on the MUO.

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“…Experimental data from our recent study using an mPGES-1 inhibitor, N -phenyl- N’ -(4-benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH, also known as 7d and MPO-0063), 39,40 has provided the very first evidence in WT animals indicating that pharmacological inhibition of mPGES-1 has promising therapeutic effects. In this study, mice underwent status epilepticus (SE) induced by pilocarpine for 1 h, after which seizure activity was terminated with diazepam.…”

Section: Epilepsymentioning

confidence: 99%

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders

Sluter

Yasmen

et al. 2023

Exp Biol Med (Maywood)

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The cyclooxygenase (COX)/prostaglandin E2 (PGE2) signaling pathway has emerged as a critical target for anti-inflammatory therapeutic development in neurological diseases. However, medical use of COX inhibitors in the treatment of various neurological disorders has been limited due to well-documented cardiovascular and cerebrovascular complications. It has been widely proposed that modulation of downstream microsomal prostaglandin E synthase-1 (mPGES-1) enzyme may provide more specificity for inhibiting PGE2-elicited neuroinflammation. Heightened levels of mPGES-1 have been detected in a variety of brain diseases such as epilepsy, stroke, glioma, and neurodegenerative diseases. Subsequently, elevated levels of PGE2, the enzymatic product of mPGES-1, have been demonstrated to modulate a multitude of deleterious effects. In epilepsy, PGE2 participates in retrograde signaling to augment glutamate release at the synapse leading to neuronal death. The excitotoxic demise of neurons incites the activation of microglia, which can become overactive upon further stimulation by PGE2. A selective mPGES-1 inhibitor was able to reduce gliosis and the expression of proinflammatory cytokines in the hippocampus following status epilepticus. A similar mechanism has also been observed in stroke, where the overactivation of microglia by PGE2 upregulated the expression and secretion of proinflammatory cytokines. This intense activation of neuroinflammatory processes triggered the secondary injury commonly observed in stroke, and blockade of mPGES-1 reduced infarction size and edema, suppressed induction of proinflammatory cytokines, and improved post-stroke well-being and cognition. Furthermore, elevated levels of PGE2 have been shown to intensify the proliferation of glioma cells, mediate P-glycoprotein expression at the blood-brain barrier (BBB) and facilitate breakdown of the BBB. For these reasons, targeting mPGES-1, the central and inducible enzyme of the COX cascade, may provide a more specific therapeutic strategy for treating neuroinflammatory diseases.

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

Cited by 13 publications

References 51 publications

Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective

Off-Label Use of Crisdesalazine (GedaCure) in Meningoencephalitis in Two Dogs

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders

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