In vivo activation of N-methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E(2) extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms.
Cyclooxygenases (COX) are a family of enzymes involved in the biosynthesis of prostaglandin (PG) and thromboxanes. The inducible enzyme cyclooxygenase-2 (COX-2) is the major isoform found in normal brain, where it is constitutively expressed in neurons and is further up-regulated during several pathological events, including seizures and ischaemia. Emerging evidence suggests that COX-2 is implicated in excitotoxic neurodegenerative phenomena. It remains unclear whether PGs or other products associated to COX activity take part in these processes. Indeed, it has been suggested that reactive oxygen species, produced by COX, could mediate neuronal damage. In order to obtain direct evidence of free radical production during COX activity, we undertook an in vivo microdialysis study to monitor the levels of PGE(2) and 8-epi-PGF(2alpha) following infusion of N-methyl-D-aspartate (NMDA). A 20-min application of 1 mm NMDA caused an immediate, MK-801-sensitive increase of both PGE(2) and 8-epi-PGF(2alpha) basal levels. These effects were largely prevented by the specific cytosolic phospholipase A(2) (cPLA(2) ) inhibitor arachidonyl trifluoromethyl ketone (ATK), by non- selective COX inhibitors indomethacin and flurbiprofen or by the COX-2 selective inhibitor NS-398, suggesting that the NMDA-evoked prostaglandin synthesis and free radical-mediated lipid peroxidation are largely dependent on COX-2 activity. As several lines of evidence suggest that prostaglandins may be potentially neuroprotective, our findings support the hypothesis that free radicals, rather than prostaglandins, mediate the toxicity associated to COX-2 activity.
Pepicelli
O
O
Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genova, Genoa, Italy.
Fedele
E
E
Bonanno
G
G
Raiteri
M
M
Ajmone-Cat
M A
MA
Greco
A
A
Levi
G
G
Minghetti
L
L
D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D028441:F2-Isoprostanes / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000008:administration & dosage; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D028441:F2-Isoprostanes; D016194:Receptors, N-Methyl-D-Aspartate; C075750:8-epi-prostaglandin F2alpha; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone