Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor κB-mediated mechanisms

Abstract

The underlying mechanisms by which physical or psychological stress causes neurodegeneration are still unknown. We have demonstrated that the high-output and long-lasting synthesizing source of nitric oxide (NO), inducible NO synthase (iNOS), is expressed in brain cortex during stress and that its overexpression accounts for the neurodegenerative changes seen after 3 weeks of repeated stress. Now we have found that acute stress (restraint for 6 h) increases the activity of a calcium-independent NOS and induces the expression of iNOS in brain cortex in adult male rats. In order to elucidate the possible mechanisms involved in this induction, we studied the role of transcription nuclear factor κB (NF-κB), which is required for iNOS synthesis. We have observed that an acute restraint stress session stimulates the translocation of the NF-κB to the nucleus after 4 h and that the administration of the NF-κB inhibitor pyrrolidine dithiocarbamate [PDTC, 75 and 150 mg/kg intraperitoneally (i.p.)] at the onset of stress inhibits the stress-induced increase in iNOS expression. Since glutamate release and subsequent NMDA (N-methyl-D-aspartate) receptor activation has been recognized as an early change after exposure to stressful stimuli, and glutamate has been shown to induce iNOS in brain via a NF-κB-dependent mechanism, we studied the possible role of excitatory amino acids in the induction of iNOS in our model. Pretreatment with the NMDA receptor antagonist dizocilpine (MK-801, 0.1 and 0.3 mg/kg i.p.) inhibits the stress-induced NF-κB activation as well as the stress-induced increase in iNOS expression. Taken together, these findings indicate that excitatory amino acids and subsequent activation of NF-κB account for stress-induced iNOS expression in cerebral cortex, and support a possible neuroprotective role for specific inhibitors in this situation.