Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Koeberle, Andreas; Werz, Oliver

doi:10.1016/j.bcp.2015.06.022

Cited by 112 publications

(96 citation statements)

References 113 publications

(204 reference statements)

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“…MF63 also displays 1000-fold selectivity for mPGES-1 over other prostaglandin and PGE synthases (Cote et al, 2007). Interestingly, MF63 is ineffective against native mouse and rat mPGES-1 (Xu et al, 2008), potentially due to differences in size or availability of the mPGES-1 active site between species (Koeberle and Werz, 2015); this has potentially prohibited advancement of phenanthrene imidazole inhibitor studies and clinical trials. Our data is the first to suggest that mPGES-1 inhibitors of the phenanthrene imidazole type are active against equine mPGES-1.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE 2 in an in vitro equine inflammation model

Martin

Jones

2017

Veterinary Immunology and Immunopathology

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Inhibition of prostaglandin E2 (PGE2) production effectively limits inflammation in horses, however nonspecific prostaglandin blockade via cyclooxygenase (COX) inhibition elicits deleterious gastrointestinal side effects in equine patients. Thus, more selective PGE2 targeting therapeutics are needed to treat inflammatory disease in horses. One potential target is microsomal prostaglandin E-synthase-1 (mPGES-1), which is the terminal enzyme downstream of COX-2 in the inducible PGE2 synthesis cascade. This enzyme has yet to be studied in equine leukocytes, which play a pivotal role in equine inflammatory disease. The objective of this study was to determine if mPGES-1 is a PGE2-selective anti-inflammatory target in equine leukocytes. To evaluate this objective, leukocyte-rich plasma (LRP) was isolated from equine whole blood collected via jugular venipuncture of six healthy adult horses of mixed breeds and genders. LRP was primed with granulocyte-monocyte colony-stimulating factor (GM-CSF) and stimulated with lipopolysaccharide (LPS) in the presence or absence of an mPGES-1 inhibitor (MF63), a COX-2 inhibitor (NS-398), or a nonselective COX inhibitor (indomethacin). Following treatment, mPGES-1 and COX-2 mRNA and protein levels were measured via qPCR and western blot, respectively, and PGE2, thromboxane (TXA2) and prostacyclin (PGI2) levels were measured in cellular supernatants via ELISA. This study revealed that LPS significantly increased mPGES-1 mRNA, but not protein levels in equine LRP as measured by qPCR and western blot, respectively. In contrast, COX-2 mRNA and protein were coordinately induced by LPS. Importantly, treatment of LPS-stimulated leukocytes with indomethacin and NS-398 significantly reduced extracellular concentrations of multiple prostanoids (PGE2, TXA2 and PGI2), while the mPGES-1 inhibitor MF63 selectively inhibited PGE2 production only. mPGES-1 inhibition also preserved higher basal levels of PGE2 production when compared to either COX inhibitor, which might be beneficial in a clinical setting. In conclusion, this work identifies mPGES-1 as a key regulator of PGE2 production and a PGE2-selective target in equine leukocytes. This study demonstrates that mPGES-1 is a potentially safer and effective therapeutic target for treatment of equine inflammatory disease when compared to traditional non-steroidal anti-inflammatory drugs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE 2 in an in vitro equine inflammation model

Martin

Jones

2017

Veterinary Immunology and Immunopathology

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“…mPGES-1 promotes inflammatory and pain reactions via synthesis of PGE 2 in a disease model of human rheumatoid arthritis [121]. In the CNS, mPGES-1 is upregulated in pyramidal neurons of AD human patients and transgenic mice [122–124], and contributes to pathogenesis of AD [123, 124]. In addition, mPGES-1 exacerbates inflammation and demyelination via disrupting the local vessel structure in a model of multiple sclerosis [125].…”

Section: Other Potential Anti-inflammatory Targets For Small Moleculesmentioning

confidence: 99%

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

Dey

Jiang

et al. 2016

Trends in Pharmacological Sciences

175

132

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As a crucial component of brain innate immunity, neuroinflammation initially contributes to neuronal tissue repair and maintenance. However, chronic inflammatory processes within the brain and associated blood-brain barrier impairment often cause neurotoxicity and hyperexcitability. Mounting evidence points to a mutual facilitation between inflammation and epilepsy, suggesting that blocking the undesired inflammatory signaling within the brain might provide novel strategies to treat seizures and epilepsy. Neuroinflammation is primarily characterized by the upregulation of proinflammatory mediators in epileptogenic foci, among which, cyclooxygenase-2/prostaglandin E2, interleukin-1β, transforming growth factor-β, toll-like receptor 4, high-mobility group box 1, and tumor necrosis factor-α have been extensively studied. Small molecules that specifically target these key proinflammatory perpetrators have been evaluated for antiepileptic and antiepileptogenic effects in animal models. These important preclinical studies provide new insights into the regulation of inflammation in epileptic brains and guide drug discovery efforts aimed at developing novel anti-inflammatory therapies for seizures and epilepsy.

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“…The protein consists of 152 amino acid residues with about 80% similarity to the enzyme in mouse, rat, or cow [7]. Owing to the undesirable effects of COX-2 selective inhibitors, interest has been focused on mPGES-1 as an alternative target for the development of analgesics and anti-inflammatory drugs [8]. The thought was that the analgesic efficacy would be largely, if not totally, conserved by PGE 2 suppression while most of the cardiovascular risk would be minimized by conserving or even boosting the cardioprotective PGI 2 production [9].…”

Section: Introductionmentioning

confidence: 99%

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE₂ Receptors in Cardiovascular Health and Diseases

Yang

2016

Oxidative Medicine and Cellular Longevity

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Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) selective inhibitors, are among the most widely used drugs to treat pain and inflammation. However, clinical trials have revealed that these inhibitors predisposed patients to a significantly increased cardiovascular risk, consisting of thrombosis, hypertension, myocardial infarction, heart failure, and sudden cardiac death. Thus, microsomal prostaglandin E (PGE) synthase-1 (mPGES-1), the key terminal enzyme involved in the synthesis of inflammatory prostaglandin E2 (PGE2), and the four PGE2 receptors (EP1–4) have gained much attention as alternative targets for the development of novel analgesics. The cardiovascular consequences of targeting mPGES-1 and the PGE2 receptors are substantially studied. Inhibition of mPGES-1 has displayed a relatively innocuous or preferable cardiovascular profile. The modulation of the four EP receptors in cardiovascular system is diversely reported as well. In this review, we highlight the most recent advances from our and other studies on the regulation of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular function, with a particular emphasis on blood pressure regulation, atherosclerosis, thrombosis, and myocardial infarction. This might lead to new avenues to improve cardiovascular disease management strategies and to seek optimized anti-inflammatory therapeutic options.

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Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Cited by 112 publications

References 113 publications

Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE 2 in an in vitro equine inflammation model

Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE 2 in an in vitro equine inflammation model

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE₂ Receptors in Cardiovascular Health and Diseases

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Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Cited by 112 publications

References 113 publications

Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE 2 in an in vitro equine inflammation model

Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE 2 in an in vitro equine inflammation model

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE2 Receptors in Cardiovascular Health and Diseases

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Product

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An Update of Microsomal Prostaglandin E Synthase‐1 and PGE₂ Receptors in Cardiovascular Health and Diseases