Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms.
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 kappaB (NF-kappaB), which is required for iNOS synthesis. We have observed that an acute restraint stress session stimulates the translocation of the NF-kappaB to the nucleus after 4 h and that the administration of the NF-kappaB 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-kappaB-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-kappaB 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-kappaB account for stress-induced iNOS expression in cerebral cortex, and support a possible neuroprotective role for specific inhibitors in this situation.
Madrigal
J L
JL
Departmento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
Moro
M A
MA
Lizasoain
I
I
Lorenzo
P
P
Castrillo
A
A
Boscá
L
L
Leza
J C
JC
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D016328:NF-kappa B; D011759:Pyrrolidines; D017470:Receptors, Glutamate; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D018698:Glutamic Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat