title: Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2.
abstract: Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and up-regulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia. Using rat models for SD and focal ischemia we investigated the expression of cyclooxygenase-1 (COX-1), the constitutive form, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme in prostaglandin biosynthesis and the target enzymes for nonsteroidal anti-inflammatory drugs. Whereas COX-1 mRNA levels were undetectable and uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia. The cortical induction was reduced by MK-801, an N-methyl-D-aspartic acid-receptor antagonist, and by dexamethasone and quinacrine, phospholipase A2 (PLA2) inhibiting compounds. MK-801 acted by blocking SD whereas treatment with PLA2 inhibitors preserved the wave propagation. NBQX, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-receptor antagonist, did not affect the SD-induced COX-2 expression, whereas COX-inhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, NG-nitro-L-arginine methyl ester, tended to enhance the COX-2 mRNA expression. In addition, ischemia induced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells. Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-D-aspartic acid-receptors and PLA2, most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.
authors.affiliation: A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Miettinen
authors.forename: F R
authors.initials: FR
authors.lastname: Fusco
authors.forename: J
authors.initials: J
authors.lastname: Yrjänheikki
authors.forename: R
authors.initials: R
authors.lastname: Keinänen
authors.forename: T
authors.initials: T
authors.lastname: Hirvonen
authors.forename: R
authors.initials: R
authors.lastname: Roivainen
authors.forename: M
authors.initials: M
authors.lastname: Närhi
authors.forename: T
authors.initials: T
authors.lastname: Hökfelt
authors.forename: J
authors.initials: J
authors.lastname: Koistinaho
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D003342:Corpus Striatum / Q000201:enzymology; D013181:Cortical Spreading Depression / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007839:Functional Laterality; D006624:Hippocampus / Q000201:enzymology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011796:Quinacrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D008565:Membrane Proteins; D011810:Quinoxalines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016291:Dizocilpine Maleate; D003907:Dexamethasone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine