In vitro and in vivo neuroprotective effect of novel mPGES-1 inhibitor in animal model of Parkinson’s disease

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

doi:10.1016/j.bmcl.2022.128920

Cited by 4 publications

(6 citation statements)

References 25 publications

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“…Interestingly, mPGES-1 is also involved in the pathogenesis of PD, which is characterized by the loss of dopaminergic neurons in the substantia nigra of the striatum. Increased expression of mPGES-1 in dopaminergic neurons has been reported in both human and animal models of PD, 18,19 and mPGES-1 inhibition led to a reduction in PGE 2 secreted by neurons that were stimulated with 6-OHDA. 73 In vitro data revealed that mPGES-1 promotes dopaminergic neuronal death through excessive production of PGE 2 .…”

Section: Neurodegenerative Diseasesmentioning

confidence: 87%

“…19 Consistent with this finding, a selective inhibitor of mPGES-1 significantly increased cell survival after 6-OHDA treatment in vitro and attenuated motor impairments and dopaminergic neuronal damage in vivo . 18 These findings suggest that mPGES-1 is a critical mediator in the pathology of PD.…”

Section: Neurodegenerative Diseasesmentioning

confidence: 90%

“…Recently, we reported that the upregulation of mPGES-1 led to excess PGE 2 production in stroke and epilepsy models, which might perpetuate secondary injuries associated with neuroinflammation 8 and excitotoxicity, 9 respectively. Moreover, upregulated mPGES-1 expression has been found in a wide range of brain diseases such as epilepsy, 10–12 glioma, 13 stroke, 14 Alzheimer’s disease, 15–17 and Parkinson’s disease, 18,19 highlighting the therapeutic potential of its modulation in treating these devastating disorders.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Neurodegenerative Diseasesmentioning

confidence: 87%

Section: Neurodegenerative Diseasesmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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

Sluter

Yasmen

et al. 2023

Exp Biol Med (Maywood)

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“…Continuing our research for the discovery of novel mPGES-1 inhibitors, we recently reported that phenylsulfonyl hydrazide derivative MPO-0144 inhibited LPSinduced PGE 2 production (IC 50 : 41.77 nM) in RAW 264.7 cells via the inhibition of murine mPGES-1 enzyme (IC 50 : 1.16 nM) as shown in Figure 1 [15][16][17]. MPO-0144 exhibited in vitro and in vivo strong neuroprotective efects in the animal model of Parkinson's disease via this mechanism of action [17]. Based on in vitro and in vivo results, herein, we investigated the anti-infammatory properties of MPO-0144 in adjuvant-induced arthritis (AIA) rodent models.…”

Section: Introductionmentioning

confidence: 94%

“…Te synthetic method of phenylsulfonyl hydrazide derivative MPO-0144 was recently reported by our group [17].…”

Section: Synthesis Of Mpo-0144mentioning

confidence: 99%

Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model

Kim,

Lee,

Kim

et al. 2024

Journal of Chemistry

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Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model.

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Unraveling brain diseases: The promise of brain-on-a-chip models

Cerutti,

Brofiga

2024

Journal of Neuroscience Methods

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In vitro and in vivo neuroprotective effect of novel mPGES-1 inhibitor in animal model of Parkinson’s disease

Cited by 4 publications

References 25 publications

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

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

Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model

Unraveling brain diseases: The promise of brain-on-a-chip models

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