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 kB (NF-kB), which is required for iNOS synthesis. We have observed that an acute restraint stress session stimulates the translocation of the NF-kB to the nucleus after 4 h and that the administration of the NF-kB 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-kB-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-kB activation as well as the stress-induced increase in iNOS expression. Taken together, these ®ndings indicate that excitatory amino acids and subsequent activation of NF-kB account for stress-induced iNOS expression in cerebral cortex, and support a possible neuroprotective role for speci®c inhibitors in this situation. Keywords: dizocilpine (MK-801), inducible nitric oxide synthase, nuclear factor-kB, restraint stress.

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

“…The effect of PDTC decreasing stress-induced accumulation of PGE 2 and COX-2 protein described in this paper suggests the involvement of NF-kB mechanisms. This might be an important mechanism since it has been demonstrated that NF-kB is activated in the brain after acute stress and accounts for NOS-2 expression in this model (Madrigal et al, 2001a) contributing to the oxidative status observed in this condition. On the other hand, it is possible also that locally produced lipid peroxidation products mediate COX-2 activity and expression.…”

“…Selected groups of rats received PDTC (pyrrolidine dithiocarbamate, an inhibitor of the activation of NF-kB; Schreck et al, 1992) or MK-801 ([(+)-5-methyl-10,11-dihydroxy-5H-dibenzo (a,d) cyclohepten-5,10-imine]; dizocilpine), a specific noncompetitive N-methyl-D-aspartate (NMDA) antagonist (Wong et al, 1988). PDTC and MK-801 were administered at the onset of the stress and at doses used to reduce oxidative status in previous papers using this model (Madrigal et al, 2001a). Each experimental group contains six to eight animals.…”

A cluster of differentially expressed signal transduction genes identified by microarray analysis in a rat genetic model of alcoholism

“…Several neurotransmitter receptors, including NMDA, beta-2-adrenergic and CB1 receptors, can induce MAPK and stress-activated protein kinase (SAPK) MAPK cascades. [25][26][27][28] We have previously reported that this pathway is activated in the cingulate cortex of another animal model characterized by persistently increased voluntary ethanol consumption and preference. 9 One of the genes detected in that model, Mapk9, was also upregulated in the Data represent expression estimates (mean7SEM) from individual arrays (n ¼ 3/strain) analysed by dChip software as described in the Materials and method section.…”

An inflammatory review of glucocorticoid actions in the CNS

“…Moreover, peripheral and central nervous system (CNS) levels of proinflammatory cytokines such as IL-1β are increased following an acute stressor in both rats and humans (Deinzer et al 2004). Additionally, the activity of NFκB and expression of NFκB target genes increase following acute stress in human peripheral blood mononuclear cells (Bierhaus et al 2003) and rat cortex (Madrigal et al 2001). These studies all concluded that acute stress enhanced the response to a subsequent immune challenge.…”