title: Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity.
abstract: In previous studies we found that neuronal overexpression of human cyclooxygenase (COX)-2 in transgenic mice potentiated excitotoxicity in vivo and in vitro. To clarify the molecular mechanisms involved in COX-2-mediated potentiation of excitotoxicity, we used cDNA microarray to identify candidate genes the expression of which is altered in the cerebral cortex of homozygous human hCOX-2 transgenic mice. We found that the mRNA expression of the cell cycle kinase (CDK) inhibitor-inhibitor kinase (INK) p18(INK4), a specific inhibitor of CDK 4,6, which controls the activation of the retinoblastoma (Rb) tumor suppressor protein phosphorylation, was decreased in the brain of adult hCOX-2 homozygous transgenics. Conversely, chronic treatment of the hCOX-2 transgenics with the preferential COX-2 inhibitor nimesulide reversed the hCOX-2-mediated decrease of cortical p18(INK4) mRNA expression in the brain. Further in vitro studies revealed that in primary cortico-hippocampal neurons derived from homozygous hCOX-2 transgenic mice, COX-2 overexpression accelerates glutamate-mediated apoptotic damage that is prevented by the CDK inhibitor flavoperidol. Moreover, treatment of wild-type primary cortico-hippocampal neuron cultures with the COX-2 preferential inhibitor nimesulide significantly attenuated glutamate-mediated apoptotic damage, which coincided with inhibition of glutamate-mediated pRb phosphorylation. These data indicate that hCOX-2 overexpression causes neuronal cell cycle deregulation in the brain and provides further rationale for targeting neuronal COX-2 in neuroprotective therapeutic research.
authors.affiliation: Neuroinflammation Research Laboratories of the Department of Psychiatry, the Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Mana
authors.initials: M
authors.lastname: Mirjany
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.forename: Giulio Maria
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002540:Cerebral Cortex / Q000378:metabolism; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D005419:Flavonoids; D007527:Isoenzymes; D010880:Piperidines; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; D018698:Glutamic Acid; D012694:Serine; C077990:alvocidib; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D018844:Cyclin-Dependent Kinases; C012655:nimesulide