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Cyclo‐oxygenase‐1 and ‐2 differently contribute to prostaglandin E 2 synthesis and lipid peroxidation after in vivo activation of N ‐methyl‐ d ‐aspartate receptors in rat hippocampus
Author(s) -
Pepicelli Olimpia,
Fedele Ernesto,
Berardi Maria,
Raiteri Maurizio,
Levi Giulio,
Greco Anita,
AjmoneCat Maria Antonietta,
Minghetti Luisa
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03150.x
Subject(s) - excitotoxicity , lipid peroxidation , nmda receptor , glutamate receptor , chemistry , in vivo , microdialysis , arachidonic acid , agonist , prostaglandin , pharmacology , hippocampal formation , prostaglandin e2 , biochemistry , receptor , endocrinology , oxidative stress , biology , extracellular , enzyme , microbiology and biotechnology
Using intracerebral microdialysis, we reported previously that acute in vivo activation of NMDA glutamate receptors triggers rapid and transient releases of prostaglandin E 2 (PGE 2 ) and F 2 ‐isoprostane 15‐ F 2t ‐IsoP in the hippocampus of freely moving rats. The formation of the two metabolites – produced through cyclo‐oxygenase (COX) enzymatic activity and free radical‐mediated peroxidation of arachidonic acid (AA), respectively, – was prevented by the specific NMDA antagonist MK‐801, and was largely dependent on COX‐2 activity. Here, we demonstrate that besides COX‐2, which is the prominent COX isoform in the brain and particularly in the hippocampus, the constitutive isoform, COX‐1 also contributes to prostaglandin (PG) synthesis and oxidative damage following in vivo acute activation of hippocampal NMDA glutamate receptors. The relative contribution of the two isoforms is dynamically regulated, as the COX‐2 selective inhibitor NS398 immediately prevented PGE 2 and 15‐ F 2t ‐IsoP formation during the application of NMDA, whereas the COX‐1 selective inhibitor SC560 was effective only 1 h after agonist infusion. Our data suggest that, although COX‐2 is the prominent isoform, COX‐1 activity may significantly contribute to excitotoxicity, particularly when considering the amount of lipid peroxidation associated with its catalytic cycle. We suggest that both isoforms should be considered as possible therapeutic targets to prevent brain damage caused by excitotoxicity.