Induction of Cyclooxygenase-2 Accounts for Restraint Stress-Induced Oxidative Status in Rat Brain

• Published in: Neuropsychopharmacology Vol. 28; no. 9; pp. 1579 - 1588
• Main Authors: MADRIGAL, José L. M, MORO, Maria A, LIZASOAIN, Ignacio, LORENZO, Pedro, FERNANDEZ, A. Patricia, RODRIGO, José, BOSCA, Lisardo, LEZA, Juan C
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01.09.2003; Nature Publishing Group
• Subjects: Adult and adolescent clinical studies; Animals; Antioxidants - administration & dosage; Anxiety disorders. Neuroses; Biological and medical sciences; Blotting, Western - methods; Brain - enzymology; Brain Chemistry; Calcium - physiology; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Size - drug effects; Cell Size - physiology; Corticosterone - blood; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Cytosol - drug effects; Cytosol - metabolism; Dinoprostone - metabolism; Dizocilpine Maleate - pharmacology; Drug Interactions; Electrophoretic Mobility Shift Assay - methods; Glutathione - metabolism; Immobilization - adverse effects; Immobilization - physiology; Immunohistochemistry; Isoenzymes - metabolism; Male; Malondialdehyde - analysis; Medical sciences; Miscellaneous; Neurons - cytology; Neurons - drug effects; Neurons - enzymology; Neuroprotective Agents - pharmacology; NF-kappa B - metabolism; Nitric Oxide Synthase - metabolism; Nitrobenzenes - pharmacology; Proline - administration & dosage; Proline - analogs & derivatives; Prostaglandin-Endoperoxide Synthases - metabolism; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Wistar; Stress, Physiological - enzymology; Sulfonamides - pharmacology; Thiocarbamates - administration & dosage; Time Factors; Rat; Enzyme; Pathogenesis; Cyclooxygenase 2; Rodentia; neurodegeneration; cyclooxygenase; Gene expression; Stress; Vertebrata; Restraint stress; Mammalia; Animal; oxidative status; Oxidoreductases
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/sj.npp.1300187

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.