Expression of cyclooxygenase-1/-2, microsomal prostaglandin-E synthase-1 and E-prostanoid receptor 2 and regulation of inflammatory mediators by PGE2 in the amoeboid microglia in hypoxic postnatal rats and murine BV-2 cells

Li, P.; Lu, Jiayue; Kaur, Charanjit; Sivakumar, V.; Tan, Ke; Ling, Eng‐Ang

doi:10.1016/j.neuroscience.2009.08.044

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…5a), a typical marker of classical macrophage activation. Previous studies reported that EP2 was involved in microglia iNOS expression [26, 27]. Accordingly, antagonizing EP2 reduced the expression of LPS-induced iNOS mRNA (Fig.…”

Section: Resultsmentioning

confidence: 63%

Differential expression of E-type prostanoid receptors 2 and 4 in microglia stimulated with lipopolysaccharide

Bonfill-Teixidor

Otxoa-de-Amezaga

Font-Nieves

et al. 2017

J Neuroinflammation

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BackgroundCyclooxygenase-2 (COX-2) is induced under inflammatory conditions, and prostaglandin E2 (PGE2) is one of the products of COX activity. PGE2 has pleiotropic actions depending on the activation of specific E-type prostanoid EP1-4 receptors. We investigated the involvement of PGE2 and EP receptors in glial activation in response to an inflammatory challenge induced by LPS.MethodsCultures of mouse microglia or astroglia cells were treated with LPS in the presence or absence of COX-2 inhibitors, and the production of PGE2 was measured by ELISA. Cells were treated with PGE2, and the effect on LPS-induced expression of TNF-α messenger RNA (mRNA) and protein was studied in the presence or absence of drug antagonists of the four EP receptors. EP receptor expression and the effects of EP2 and EP4 agonists and antagonists were studied at different time points after LPS.ResultsPGE2 production after LPS was COX-2-dependent. PGE2 reduced the glial production of TNF-α after LPS. Microglia expressed higher levels of EP4 and EP2 mRNA than astroglia. Activation of EP4 or EP2 receptors with selective drug agonists attenuated LPS-induced TNF-α in microglia. However, only antagonizing EP4 prevented the PGE2 effect demonstrating that EP4 was the main target of PGE2 in naïve microglia. Moreover, the relative expression of EP receptors changed during the course of classical microglial activation since EP4 expression was strongly depressed while EP2 increased 24 h after LPS and was detected in nuclear/peri-nuclear locations. EP2 regulated the expression of iNOS, NADPH oxidase-2, and vascular endothelial growth factor. NADPH oxidase-2 and iNOS activities require the oxidation of NADPH, and the pentose phosphate pathway is a main source of NADPH. LPS increased the mRNA expression of the rate-limiting enzyme of the pentose pathway glucose-6-phosphate dehydrogenase, and EP2 activity was involved in this effect.ConclusionsThese results show that while selective activation of EP4 or EP2 exerts anti-inflammatory actions, EP4 is the main target of PGE2 in naïve microglia. The level of EP receptor expression changes from naïve to primed microglia where the COX-2/PGE2/EP2 axis modulates important adaptive metabolic changes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0780-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 63%

Differential expression of E-type prostanoid receptors 2 and 4 in microglia stimulated with lipopolysaccharide

Bonfill-Teixidor

Otxoa-de-Amezaga

Font-Nieves

et al. 2017

J Neuroinflammation

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“…injected with a single dose of LPS (3 mg/kg) and received vehicle (normal saline) orally 1 h before the LPS injection. The ginsenoside Rg 3 treatment groups [LPS+ Rg 3 (10), LPS+ Rg 3 (20), LPS+ Rg 3 (30)] were administered 3 oral doses of ginsenoside Rg 3 (10,20, or 30 mg/kg, dissolved in normal saline) once 1 h prior to LPS injection. A total of 48 mice were used in this study.…”

Section: Methodsmentioning

confidence: 99%

“…29) Nitric oxide (NO) and prostaglandins are major pleiotrophic mediators produced by iNOS, COX-1 and COX-2. 29,30) Microglia can generate superoxide, by using the constitutively expressed NADPH oxidase, which reacts with NO to form the powerful oxidant peroxynitrite. 31) Cyclooxygenase plays a central role in the inflammatory cascade by converting arachidonic acid into bioactive prostanoids.…”

Section: Effect Of Ginsenoside Rg 3 On Microglia Activation In the mentioning

confidence: 99%

Ginsenoside Rg<sub>3</sub> Attenuates Microglia Activation Following Systemic Lipopolysaccharide Treatment in Mice

Park

Choi

Sohn

et al. 2012

Biological & Pharmaceutical Bulletin

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“…EP2 receptor activation on microglia causes induction of proinflammatory cytokines and other mediators (25). We studied EP2-mediated induction of COX-2 because induction is rapid and large in comparison with other inflammatory mediators.…”

Section: And Fig 2 E and F)mentioning

confidence: 99%

Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2

Jiang¹,

Ganesh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

101

194

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With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, prostaglandin receptors provide alternative targets for the treatment of COX-2-mediated pathological conditions in both the periphery and the central nervous system. Activation of prostaglandin E2 receptor (PGE 2 ) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the prostaglandin EP2 receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 receptor with K B 2-20 nM in Schild regression analysis and 268-to 4,730-fold selectivity over the prostaglandin EP4 receptor. A brain-permeant compound completely suppressed the up-regulation of COX-2 mRNA in rat cultured microglia by EP2 activation and significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of this novel group of antagonists raise the possibility that selective block of EP2 signaling via small molecules can be an innovative therapeutic strategy for inflammation-related brain injury.yclooxygenase-2 (COX-2), the inducible isoform of COX, is rapidly up-regulated in damaged tissue, for example in the central nervous system (CNS) after a seizure or cerebral ischemia (1-3). COX-2 induction in CNS overall contributes to inflammation and injury mainly by producing prostanoids (4-7). However, the deleterious cardio-and cerebrovascular side effects from sustained inhibition of COX-2 suggest that some COX-2 downstream prostanoid signaling might be beneficial (8), such that modulation of a specific prostanoid receptor or synthase could be a superior therapeutic strategy compared with generic block of the entire COX-2 cascade. Prostaglandin E2 (PGE 2 ), a dominant enzymatic product of COX-2 in the brain, can activate four Gprotein-coupled receptors (GPCRs): EP1, EP2, EP3, and EP4. Among these, EP2 and EP4 receptors are positively coupled through Gαs to cAMP production (9). In turn, cAMP can initiate multiple downstream events mediated by protein kinase A (PKA) or exchange protein activated by cAMP (Epac) (9).The EP2 receptor is widely expressed in both neurons and glia (3, 10). Neuronal EP2 activation appears to mediate some beneficial effects, such as PKA-dependent neuroprotection in acute models of ischemia and excitotoxicity (3,11,12), early neuroprotection following seizures (13), and promotion of spatial learning (14). Conversely, on the basis of the phenotype of EP2 knockout mice, EP2 activation is thought to promote inflammation and neurotoxicity in animal models of neurodegenerative diseases including Alzheimer's disease (15), Parkinson's disease (16), and amyotrophic lateral sclerosis (10). Glial, especially microglial EP2, is considered to play a major role in brain inflammation associated with chronic ne...

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Expression of cyclooxygenase-1/-2, microsomal prostaglandin-E synthase-1 and E-prostanoid receptor 2 and regulation of inflammatory mediators by PGE2 in the amoeboid microglia in hypoxic postnatal rats and murine BV-2 cells

Cited by 24 publications

References 46 publications

Differential expression of E-type prostanoid receptors 2 and 4 in microglia stimulated with lipopolysaccharide

Differential expression of E-type prostanoid receptors 2 and 4 in microglia stimulated with lipopolysaccharide

Ginsenoside Rg<sub>3</sub> Attenuates Microglia Activation Following Systemic Lipopolysaccharide Treatment in Mice

Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2

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