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Inhibiting the PGE₂ Receptor EP2 Mitigates Excitotoxicity and Ischemic Injury.

ABSTRACT: Prostaglandin E2 (PGE₂) is elevated in the brain by excitotoxic insults and, in turn, aggravates the neurotoxicity mainly through acting on its Gα_s-coupled receptor EP2, inspiring a therapeutic strategy of targeting this key proinflammatory pathway. Herein, we investigated the effects of several highly potent and selective small-molecule antagonists of the EP2 receptor on neuronal excitotoxicity both in vitro and in vivo. EP2 inhibition by these novel compounds largely decreased the neuronal injury in rat primary hippocampal cultures containing both neurons and glia that were treated with N-methyl-d-aspartate and glycine. Using a bioavailable and brain-permeant analogue TG6-10-1 that we recently developed to target the central EP2 receptor, we found that the poststroke EP2 inhibition in mice decreased the neurological deficits and infarct volumes as well as downregulated the prototypic inflammatory cytokines in the brain after a transient ischemia. Our preclinical findings together reinforced the notion that targeting the EP2 receptor represents an emerging therapeutic strategy to prevent the neuronal injury and inflammation following ischemic stroke.

SUBMITTER: Li L

PROVIDER: S-EPMC7432651 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Inhibiting the PGE2 Receptor EP2 Mitigates Excitotoxicity and Ischemic Injury.

Li Lexiao L Yu Ying Y Hou Ruida R Hao Jiukuan J Jiang Jianxiong J

ACS pharmacology & translational science 20200625 4

Prostaglandin E2 (PGE2) is elevated in the brain by excitotoxic insults and, in turn, aggravates the neurotoxicity mainly through acting on its Gαs-coupled receptor EP2, inspiring a therapeutic strategy of targeting this key proinflammatory pathway. Herein, we investigated the effects of several highly potent and selective small-molecule antagonists of the EP2 receptor on neuronal excitotoxicity both in vitro and in vivo. EP2 inhibition by these novel compounds largely decr ...[more]

PMID: 32832866

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Project description:BackgroundThe steroid hormone estrogen (17-β-estradiol, E2) provides neuroprotection against cerebral ischemic injury by activating estrogen receptors. The novel estrogen receptor G protein-coupled receptor 30 (GPR30) is highly expressed in the brain and provides acute neuroprotection against stroke. However, the underlying mechanisms remain unclear.MethodsIn this study, ovariectomized female mice were subjected to middle cerebral artery occlusion (MCAO), and E2, G1, and ICI182780 were administered immediately upon reperfusion. The infarction volume, neurological scores, and neuronal injuries were examined. Primary microglial cells were subjected to oxygen-glucose deprivation (OGD), and the drugs were administered immediately upon reintroduction. The pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in penumbra and microglia were assessed by ELISA. The cell viability and lactose dehydrogenase (LDH) release of neurons co-cultured with microglia were analyzed using cell counting kit-8 (CCK8) and LDH release assays. Microglial activation as well as GPR30, Iba1, and Toll-like receptor 4 (TLR4) protein expression and TLR4 mRNA expression were detected. Additionally, NF-κB activity was detected in lipopolysaccharide (LPS)-activated microglia after the activation of GPR30.ResultsGPR30 was highly expressed in microglia and significantly increased after ischemic injury. The activation of GPR30 significantly reduced the infarction volume, improved the neurological deficit, and alleviated neuronal injuries. Moreover, GPR30 activation significantly reduced the release of TNF-α, IL-1β, and IL-6 from ischemic penumbra and microglia subjected to OGD and alleviated neuronal injury as assessed using the CCK8 and LDH assays. Finally, the activation of GPR30 relieved microglial activation, reduced Iba1 and TLR4 protein expression and TLR4 mRNA levels, and inhibited NF-κB activity.ConclusionsMicroglial GPR30 exerts acute neuroprotective effects by inhibiting TLR4-mediated microglial inflammation, which indicates that GPR30 may be a potential target for the treatment of ischemic stroke.

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Inhibiting the PGE₂ Receptor EP2 Mitigates Excitotoxicity and Ischemic Injury.

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Inhibiting the PGE<sub>2</sub> Receptor EP2 Mitigates Excitotoxicity and Ischemic Injury.

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