Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2

Susanna Miettinen, Francesca R. Fusco, Juha Yrjänheikki, Riitta Keinänen, Timo Hirvonen, Reina Roivainen, Matti Närhi, Tomas Hökfelt, Jari Koistinaho

Research output: Contribution to journalArticle

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Abstract

Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and upregulation 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 α-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, N(G)-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.

Original languageEnglish
Pages (from-to)6500-6505
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number12
DOIs
Publication statusPublished - Jun 10 1997

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Phospholipases A2
N-Methylaspartate
Cyclooxygenase 2
Brain Ischemia
Ischemia
Neurons
Cyclooxygenase 1
Dizocilpine Maleate
Messenger RNA
Phospholipase A2 Inhibitors
Kainic Acid Receptors
Corpus Striatum
Quinacrine
Diclofenac
NG-Nitroarginine Methyl Ester
Enzymes
Nitric Oxide Synthase
Indomethacin
Astrocytes
Dexamethasone

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2 . / Miettinen, Susanna; Fusco, Francesca R.; Yrjänheikki, Juha; Keinänen, Riitta; Hirvonen, Timo; Roivainen, Reina; Närhi, Matti; Hökfelt, Tomas; Koistinaho, Jari.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 12, 10.06.1997, p. 6500-6505.

Research output: Contribution to journalArticle

Miettinen, Susanna ; Fusco, Francesca R. ; Yrjänheikki, Juha ; Keinänen, Riitta ; Hirvonen, Timo ; Roivainen, Reina ; Närhi, Matti ; Hökfelt, Tomas ; Koistinaho, Jari. / Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2 . In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 12. pp. 6500-6505.
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AU - Fusco, Francesca R.

AU - Yrjänheikki, Juha

AU - Keinänen, Riitta

AU - Hirvonen, Timo

AU - Roivainen, Reina

AU - Närhi, Matti

AU - Hökfelt, Tomas

AU - Koistinaho, Jari

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