title: Activation of nuclear factor kappaB by nitric oxide in rat striatal neurones: differential inhibition of the p50 and p65 subunits by dexamethasone.
abstract: Nitric oxide (NO), an intercellular messenger in the brain, has been implicated in both neuronal plasticity and neurotoxicity. It has been suggested that NO can activate the DNA binding activity of nuclear factor kappaB (NF-kappaB) family proteins in some cell types while having an inhibitory effect in others. In this study we have investigated the effect of acute NO in primary neuronal cultures of rat striatum using immunohistochemistry. Exposure of neurones to the NO-mimetic S-nitroso-n-acetylpenicillamine (SNAP; 200 microM) and to bacterial lipopolysaccharide (LPS; 10 microg/ml) for 30 min increased nuclear protein expression of the p50 subunit of NF-kappaB. SNAP also enhanced nuclear protein expression of the p65 subunit of NF-kappaB. Simultaneously, the cytoplasmic expression of phosphorylated inhibitory protein IkappaB alpha was dramatically increased by SNAP (200 microM), LPS (10 microg/ml), and kainate (50 microM) treatment. In the adult rat, stimulation with NOR-3 (2 mg/kg), a NO donor, increased NF-kappaB DNA binding activity in the striatum after 45 min. Because glucocorticoids inhibit NF-kappaB activity, primary cultures were pretreated with dexamethasone (50 microM) before SNAP, LPS, and kainate treatment, and the effect on the protein expression level of the individual subunits p50 and p65 present in the classical form of the transcription factor NF-kappaB was assessed. Dexamethasone pretreatment resulted in a marked reduction of p65 protein in striatal neurones after SNAP, LPS, and kainate, whereas p50 expression was reduced by dexamethasone pretreatment only after an LPS stimulus. This study indicates that NO-releasing compounds can directly induce nuclear NF-kappaB subunit expression in rat striatum and that glucocorticoids selectively inhibit p65 subunit expression following exposure to NO.
authors.affiliation: Department of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Simpson
authors.forename: B J
authors.initials: BJ
authors.lastname: Morris
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D020672:I-kappa B Proteins; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D003907:Dexamethasone; D010396:Penicillamine; D007608:Kainic Acid