Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of cyclooxygenase-2 (COX-2) with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of prostaglandins protect neurons in rodent models of cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional prostaglandin receptors not previously characterized in organotypic models of glutamate excitotoxicity. We find that PGD(2), PGI(2), and PGF(2alpha) receptors protect motor neurons in an organotypic spinal cord model of amyotrophic lateral sclerosis (ALS). In addition, PGI(2) and TXA(2) receptors rescue CA1 neurons in an organotypic hippocampal model of N-methyl-d-aspartate excitotoxicity. However, in a model of inflammation induced by lipopolysaccharide, prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or inflammation predominates as the underlying toxic stimulus.
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PMID:Divergent effects of prostaglandin receptor signaling on neuronal survival. 1757 54

Induction of COX-2 activity in cerebral ischemia results in increased neuronal injury and infarct size. Recent studies investigating neurotoxic mechanisms of COX-2 demonstrate both toxic and paradoxically protective effects of downstream prostaglandin receptor signaling pathways. We tested whether misoprostol, a PGE(2) receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE(2) EP2, EP3, and EP4 receptors, would reduce brain injury in the murine middle cerebral artery occlusion-reperfusion (MCAO-RP) model. Administration of misoprostol, at the time of MCAO or 2h after MCAO, resulted in significant rescue of infarct volume at 24 and 72h. Immunocytochemistry demonstrated dynamic regulation of the EP2 and EP4 receptors during reperfusion in neurons and endothelial cells of cerebral cortex and striatum, with limited expression of EP3 receptor. EP3-/- mice had no significant changes in infarct volume compared to control littermates. Moreover, administration of misoprostol to EP3+/+ and EP3-/- mice showed similar levels of infarct rescue, indicating that misoprostol protection was not mediated through the EP3 receptor. Taken together, these findings suggest a novel function for misoprostol as a protective agent in cerebral ischemia acting via the PGE(2) EP2 and/or EP4 receptors.
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PMID:Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia. 1847 36

This review presents an overview of the emerging field of prostaglandin signaling in neurological diseases, focusing on PGE(2) signaling through its four E-prostanoid (EP) receptors. A large number of studies have demonstrated a neurotoxic function of the inducible cyclooxygenase COX-2 in a broad spectrum of neurological disease models in the central nervous system (CNS), from models of cerebral ischemia to models of neurodegeneration and inflammation. Since COX-1 and COX-2 catalyze the first committed step in prostaglandin synthesis, an effort is underway to identify the downstream prostaglandin signaling pathways that mediate the toxic effect of COX-2. Recent epidemiologic studies demonstrate that chronic COX-2 inhibition can produce adverse cerebrovascular and cardiovascular effects, indicating that some prostaglandin signaling pathways are beneficial. Consistent with this concept, recent studies demonstrate that in the CNS, specific prostaglandin receptor signaling pathways mediate toxic effects in brain but a larger number appear to mediate paradoxically protective effects. Further complexity is emerging, as exemplified by the PGE(2) EP2 receptor, where cerebroprotective or toxic effects of a particular prostaglandin signaling pathway can differ depending on the context of cerebral injury, for example, in excitotoxicity/hypoxia paradigms versus inflammatory-mediated secondary neurotoxicity. The divergent effects of prostaglandin receptor signaling will likely depend on distinct patterns and dynamics of receptor expression in neurons, endothelial cells, and glia and the specific ways in which these cell types participate in particular models of neurological injury.
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PMID:Emerging roles of PGE2 receptors in models of neurological disease. 2280 72