Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum

Slawik, Helen; Volk, Benedikt; Fiebich, Bernd L.; Hüll, Michael

doi:10.1016/j.neuint.2004.04.007

Cited by 46 publications

(33 citation statements)

References 42 publications

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“…Our results suggest that EP3R inhibition may affect microglia and astrocytes differently in the early period of thrombin-induced brain injury. Moreover, a prior study 42 showed that 60% of microglia expresses EP3R in striatum at 5 days after quinolinic acid injection and that this percentage increases to 80% at 10 days. In contrast, our results showed EP3R þ /CD11b þ cells in the perilesional area at 72 h after thrombin injection.…”

Section: Discussionmentioning

confidence: 90%

Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury

Han

Lan

et al. 2015

J Cereb Blood Flow Metab

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Prostaglandin E 2 EP3 receptor is the only prostaglandin E 2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68 þ microglia, but increased the number of Ym-1 þ M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E 2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase-mediated cytotoxicity and proinflammatory responses.

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Section: Discussionmentioning

confidence: 90%

Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury

Han

Lan

et al. 2015

J Cereb Blood Flow Metab

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“…It has been reported that EP3 receptors are expressed in glial cells after intrastriatal injection of quinolic acid in rats (Slawik et al, 2004). This finding implies a direct role for EP3 receptors in various neurodegenerative disorders, such as stroke and Alzheimer disease.…”

Section: Introductionmentioning

confidence: 79%

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

Ahmad¹,

Ahmad²,

Zhuang³

et al. 2007

Journal of Neuroimmunology

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The effect of PGE 2 EP3 receptors on injury size was investigated following cerebral ischemia and induced excitotoxicity in mice. Treatment with the selective EP3 agonist ONO-AE-248 significantly and dose-dependently increased infarct size in the middle cerebral artery occlusion model. In a separate experiment, pretreatment with ONO-AE-248 exacerbated the lesion caused by N-methyl-D-aspartic acid-induced acute excitotoxicity. Conversely, genetic deletion of EP3 provided protection against N-methyl-D-aspartic acid-induced toxicity. The results suggest that PGE 2 , by stimulating EP3 receptors, can contribute to the toxicity associated with cyclooxygenase and that antagonizing this receptor could be used therapeutically to protect against stroke-and excitotoxicityinduced brain damage.

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“…PGE 2 mediates its effects via four different recep-tors named EP1 through EP4 (Narumiya et al, 1999). Both EP1 and EP2 receptors are found on cultured microglia, although EP3 was also detected in activated microglia in vivo (Slawik et al, 2004). Microglia-driven chronic inflammatory responses are thus considered a major factor in the progression of neurodegenerative disorders.…”

Section: Introductionmentioning

confidence: 99%

Signal transduction pathways regulating cyclooxygenase‐2 in lipopolysaccharide‐activated primary rat microglia

Akundi

Candelario‐Jalil

Heß

et al. 2005

Glia

125

109

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Microglia are the major cell type involved in neuroinflammatory events in brain diseases such as encephalitis, stroke, and neurodegenerative disorders, and contribute significantly to the release of prostaglandins (PGs) during neuronal insults. In this report, we studied the immediate-early intracellular signalling pathways in microglia, following bacterial lipopolysaccharide (LPS) stimulation, leading to the synthesis and release of PGE2. Here we show that LPS induces cyclooxygenase (COX) 2 by activating sphingomyelinases leading to the release of ceramides, which in turn, activate the p38 mitogen-activated protein kinases (MAPK), but not the p42/44 MAPK. We further show that exogenously added ceramide analogue (C2-ceramide) also induce PGE2 synthesis through a p38 MAPK-dependent pathway. This potential nature of ceramides in activating microglia suggests that endogenously produced ceramides during neuronal apoptosis in ischemia or neurodegenerative diseases could also contribute to the amplification of neuroinflammatory events. In contrast to protein kinase C (PKC) and phosphocholine-specific phospholipase C (PC-PLC), which transcriptionally regulate LPS-induced COX-2 synthesis, inhibition of phospholipase A2 (PLA2) has no effect on COX-2 transcription, although it inhibits the release of PGE2. Transcriptional regulation of LPS-induced COX-2 by PKC is further proved by the ability of the PKC inhibitor, Gö 6976, to inhibit LPS-induced 8-isoprostane synthesis, but not affecting LPS-induced COX-2 activity. Our data with 8-isoprostane also indicates that COX-2 plays a major role in ROS production in LPS-activated microglia. This detailed view of the intracellular signaling pathway in microglial activation and COX-2 expression opens a new therapeutic window in the search for new and more effective central anti-inflammatory agents.

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Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum

Cited by 46 publications

References 42 publications

Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury

Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

Signal transduction pathways regulating cyclooxygenase‐2 in lipopolysaccharide‐activated primary rat microglia

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Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum

Cited by 46 publications

References 42 publications

Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

Signal transduction pathways regulating cyclooxygenase‐2 in lipopolysaccharide‐activated primary rat microglia

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Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury

Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury