Induction of cyclooxygenase-2 accounts for restraint stress-induced oxidative status in rat brain.
Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolism of arachidonic acid into prostanoids. Although it is constitutively expressed in brain neurons, the inducible isoform (COX-2) is also upregulated in pathological conditions such as seizures, ischemia or some degenerative diseases. To assess whether COX-2 is regulated after stress, we have used adult male Wistar rats, some of which were immobilized during 6 h. An increase in PGE2 concentration occurs in brain cortex after 2-6 h of the onset of stress as well as an enhancement of COX-2 protein. Immunohistochemical studies indicate that COX-2 is expressed in the cortex and hippocampus after stress in cells with morphology of neurons. Administration of PDTC (150 mg/kg), an inhibitor of the transcription factor NF-kappaB or MK-801 (0.2 mg/kg), an N-methyl-D-aspartate receptor blocker, prevents both stress-induced increase in COX-2 activity and protein levels, suggesting an implication of these factors in the mechanism by which stress induces COX-2 in brain. To assess if COX-2 accounts for the oxidative status seen in brain after stress, a group of animals were i.p. injected with NS-398, a specific COX-2 inhibitor 1 h prior to the onset of stress. NS-398 (5 mg/kg) decreases stress-induced malondialdehyde accumulation in cortex as well as prevents the stress-induced oxidation of glutathione. Finally, NS-398 reduced Ca2+-independent inducible nitric oxide synthase (iNOS, NOS-2) activity and lowered the stress-induced accumulation of NO metabolite levels in cortex. These effects of NS-398 seem to be due to the specific inhibition of COX-2, since it has no effect on stress-induced corticosterone release, glutamate release, and NF-kappaB activation. These findings are discussed as possible damaging and/or adaptive roles for stress-induced COX-2 in the brain.
Madrigal
José L M
JL
Department of Pharmacology, Faculty of Medicine, University of Complutense, 28040 Madrid, Spain.
Moro
María A
MA
Lizasoain
Ignacio
I
Lorenzo
Pedro
P
Fernández
A Patricia
AP
Rodrigo
José
J
Boscá
Lisardo
L
Leza
Juan C
JC
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry; D002118:Calcium / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005978:Glutathione / Q000378:metabolism; D007103:Immobilization / Q000009:adverse effects / Q000502:physiology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000201:enzymology*; D013449:Sulfonamides / Q000494:pharmacology; D013859:Thiocarbamates / Q000008:administration & dosage; D013997:Time Factors
D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009578:Nitrobenzenes; D013449:Sulfonamides; D013859:Thiocarbamates; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C066229:prolinedithiocarbamate; D008315:Malondialdehyde; D016291:Dizocilpine Maleate; D011392:Proline; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione; D015232:Dinoprostone; D002118:Calcium; D003345:Corticosterone