Abstract
Up-regulation of neuronal cyclooxygenase-2 (COX-2) and the elevation in prostaglandin E(2) (PGE(2)) have been reported to occur after cerebral ischemic insult. To evaluate whether the COX-2 reaction product PGE(2) is directly related to induction of apoptosis in neuronal cells, the effect of PGE(2) on cell viability was examined in rat cortical cells. PGE(2) induced apoptosis in a dose-dependent manner (5-25 microM) 48 h after addition to the cells, which was characterized by cell shrinkage, nuclear condensation or fragmentation, and internucleosomal DNA fragmentation. Neither 17-phenyl trinor-prostaglandin E(2) (an EP1 agonist) or sulprostone (an EP3 agonist) induced cell death, whereas butaprost (an EP2 agonist) induced apoptotic cell death. In addition, PGE(2) activated caspase-3 in a time-dependent manner until 24 h after treatment. The apoptosis induced by PGE(2) was prevented by a caspase-3 inhibitor in a dose-dependent manner. In contrast, dibutyryl cyclic adenosine monophosphate also induced apoptotic cell death in a dose-dependent manner (20-100 microM). These results suggest that PGE(2), acting via an EP2-like receptor, induces apoptosis in neurons.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Cyclases / metabolism
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Alprostadil / analogs & derivatives*
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Alprostadil / pharmacology
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Animals
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Apoptosis / drug effects*
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Brain Ischemia / metabolism
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Brain Ischemia / pathology
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Bucladesine / pharmacology
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Caspase 3
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Caspase Inhibitors
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Caspases / physiology*
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Cerebral Cortex / drug effects*
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Cerebral Cortex / enzymology
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Cerebral Cortex / pathology
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Cyclic AMP / physiology
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Cyclooxygenase 2
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Cysteine Proteinase Inhibitors / pharmacology
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Dinoprostone / analogs & derivatives*
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Dinoprostone / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Isoenzymes / physiology
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / physiology*
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Prostaglandin Antagonists / pharmacology
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Prostaglandin-Endoperoxide Synthases / physiology
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Rats
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Receptors, Prostaglandin E / antagonists & inhibitors
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Receptors, Prostaglandin E / physiology
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Receptors, Prostaglandin E, EP1 Subtype
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP3 Subtype
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Second Messenger Systems / physiology
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Signal Transduction / drug effects*
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Signal Transduction / physiology
Substances
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17-phenyltrinorprostaglandin E2
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Isoenzymes
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Nerve Tissue Proteins
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Prostaglandin Antagonists
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Ptger1 protein, rat
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Ptger2 protein, rat
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Ptger3 protein, rat
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP1 Subtype
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP3 Subtype
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sulprostone
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Bucladesine
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Cyclic AMP
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Casp3 protein, rat
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Caspase 3
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Caspases
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Adenylyl Cyclases
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Alprostadil
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butaprost
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Dinoprostone