Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity

Kawano, Takayuki; Anrather, Josef; Zhou, Ping; Park, Laibaik; Wang, Gang; Frys, Kelly; Kunz, Alexander; Cho, Sunghee; Orio, Marcello; Iadecola, Costantino

doi:10.1038/nm1362

Cited by 349 publications

(398 citation statements)

References 29 publications

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“…For example, EP2 receptor sites, despite neuroprotective capabilities at low doses [13], have been found to create a positive feedback loop by leading to further Aβ production [8]. In astrocytes, the elevated PGE 2 might also cause glutamate excitotoxicity via stimulation of the EP1 receptor [41][42][43][44]. Interestingly, in our studies mPGES-1 appeared to be up-regulated in the pyramidal neurons in advanced AD brains.…”

Section: Discussionmentioning

confidence: 47%

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Chaudhry

Zhuang

Crain

et al. 2007

Alzheimer's & Dementia

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Section: Discussionmentioning

confidence: 47%

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Chaudhry

Zhuang

Crain

et al. 2007

Alzheimer's & Dementia

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“…Similarly, PGE 2 is a well-known inflammatory mediator that is derived from arachidonic acid via the action of COX-2. COX-2 emerged as a major player in brain inflammation, and increased COX-2 expression is believed to contribute to brain injury [34] . In the present study, probucol concentrationdependently inhibited both NO and PGE 2 production via the down-regulations of iNOS and COX-2 expression at the mRNA and protein levels in the LPS-stimulated BV2 cells and primary microglia (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

et al. 2016

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Aim: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. Methods: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg -1 ·d -1 , po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. Results: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, preadministration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total-and LDL-cholesterol levels. Conclusion: Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.

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“…Larger doses of NMDA or longer exposure times could potentially show a different cPLA 2 ␣ dependence, but resulted in less stable recording conditions. Indeed, 30 M NMDA applied to mixed neuronal-glial cultures resulted in sustained Ca 2ϩ elevation that was cyclooxygenase-1-dependent (21). When acutely isolated CA1 neurons were exposed to 100 M NMDA for 10 min, a large, progressive, postexposure Na ϩ /Ca 2ϩ conductance developed that was insensitive to later blockade of NMDA receptors and that appeared to trigger cell injury (22).…”

Section: Discussionmentioning

confidence: 99%

Cytosolic phospholipase A ₂ alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment

Shen

Kishimoto

Linden³

et al. 2007

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

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The arachidonic acid-generating enzyme cytosolic phospholipase A 2 alpha (cPLA2␣) has been implicated in the progression of excitotoxic neuronal injury. However, the mechanisms of cPLA 2␣ toxicity have yet to be determined. Here, we used a model system exposing mouse hippocampal slices to NMDA as an excitotoxic injury, in combination with simultaneous patch-clamp recording and confocal Ca 2؉ imaging of CA1 pyramidal neurons. NMDA treatment caused significantly greater injury in wild-type (WT) than in cPLA 2␣ null CA1 neurons. Bath application of NMDA evoked a slow inward current in voltage-clamped neurons (composed of both NMDA receptor-mediated and other conductances) that was smaller in cPLA 2␣ null than in WT slices. This was not due to down-regulation of NMDA receptor function because NMDA receptor-mediated currents were equivalent in each genotype following brief photolysis of caged glutamate. Current-clamp recordings were made during and following NMDA exposure by eliciting a single action potential with a brief current injection. After NMDA exposure, WT CA1 neurons developed a spike-evoked plateau potential and an increased spike-evoked dendritic Ca 2؉ transient. These effects were absent in CA1 neurons from cPLA 2␣ null mice and WT neurons treated with a cPLA 2␣ inhibitor. The Ca-sensitive K-channel toxins, apamin and paxilline, caused spike broadening and Ca 2؉ enhancement in WT and cPLA2␣ null slices. NMDA application in WT and arachidonate applied to cPLA 2␣ null cells occluded the effects of apamin/paxilline. These results indicate that cPLA 2␣ activity is required for development of aberrant electrophysiologic events triggered by NMDA receptor activation, in part through attenuation of K-channel function.action potential ͉ arachidonic acid ͉ calcium ͉ excitotoxicity ͉ inhibition T he phospholipase A 2 (PLA 2 ) enzymes catalyze ester hydrolysis of fatty acids from the second position of membrane glycerophospholipids. In mammalian cells, because this sn-2 position is highly enriched with arachidonic acid (AA), the PLA 2 s are considered the major regulated source of cellular AA. Once liberated by PLA 2 s, AA can be metabolized by a number of enzymes to create the eicosanoids. These products and AA have important functions in regulating cellular homeostasis and inflammation and have been implicated in a number of neurologic injuries (1, 2).Of the PLA 2 s expressed in the brain, the enzyme cytosolic phospholipase A 2 alpha (cPLA 2 ␣) has a unique set of biochemical properties that implicate it in AA signaling in response to neuronal activity. In response to micromolar increases in intracellular Ca 2ϩ , cPLA 2 ␣ translocates from the cytosol to cellular membranes, where its phospholipid substrate resides (3). In addition, the enzymatic activity of cPLA 2 ␣ depends upon phosphorylation by p38 MAPK (4) and ERK-2 (5). cPLA 2 ␣ has a marked preference for phospholipid substrates, with AA in the second position (6). Macrophages and mast cells derived from cPLA 2 ␣-deficient mice (cPLA 2 ␣ Ϫ/Ϫ ) are unable t...

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Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity

Cited by 349 publications

References 29 publications

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

Cytosolic phospholipase A ₂ alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment

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Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity

Cited by 349 publications

References 29 publications

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

Cytosolic phospholipase A 2 alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment

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Cytosolic phospholipase A ₂ alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment