17-phenyltrinorprostaglandin-e2 and Brain-Ischemia

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.

Topics: Adenylyl Cyclases; Alprostadil; Animals; Apoptosis; Brain Ischemia; Bucladesine; Caspase 3; Caspase Inhibitors; Caspases; Cells, Cultured; Cerebral Cortex; Cyclic AMP; Cyclooxygenase 2; Cysteine Proteinase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Activation; Isoenzymes; Nerve Tissue Proteins; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Rats; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Second Messenger Systems; Signal Transduction