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

Abstract

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 PGE 2 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-kB 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 stressinduced oxidation of glutathione. Finally, NS-398 reduced Ca 2+ -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-kB activation. These findings are discussed as possible damaging and/or adaptive roles for stress-induced COX-2 in the brain.

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

“…Stress could also activate NF-κB in surrounding cells (e.g., ANPs, neurons, glia) that indirectly influence NSC proliferation. For example, stress-induced NF-κB activation results in generation of nitric oxide (NO) (26)(27)(28), and NO has been shown to inhibit neurogenesis in the adult hippocampus and to contribute to the inhibition of neurogenesis by stress (29,30).…”

Changes in Cyclooxygenase-2 Immunoreactivity in the Hippocampus in a Model of Streptozotocin-Induced Type 1 Diabetic Rats

“…In alcohol-induced brain damage, COX-2 was induced and its pattern was similar to that induced by excitatory amino acids [19], and COX-2 induction was also observed after seizure in rats [34]. Increased expression of COX-2 is reported to be related with reactive oxygen species and neuronal oxidative stress [22]. Alteration of the COX-2 pathway and oxidative stress was reported to being related with diabetic neuropathy [17].…”

Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers

“…Furthermore, inhibition of COX-2 with NS-398 attenuates restraint stress (a model of depression) induced oxidative changes. 258 The inflammatory hypothesis (distinct from the AA hypothesis) of bipolar disorder has led to a clinical trial addressing the effect of a specific COX-2 inhibitor as an adjunct treatment in bipolar patients. 259 …”