title: Influence of N-methyl-D-aspartate receptors on ouabain activation of nuclear factor-κB in the rat hippocampus.
abstract: It has been shown that ouabain (OUA) can activate the Na,K-ATPase complex and mediate intracellular signaling in the central nervous system (CNS). Inflammatory stimulus increases glutamatergic transmission, especially at N-methyl-D-aspartate (NMDA) receptors, which are usually coupled to the activation of nitric oxide synthase (NOS). Nuclear factor-κB (NF-κB) activation modulates the expression of genes involved in development, plasticity, and inflammation. The present work investigated the effects of OUA on NF-κB binding activity in rat hippocampus and the influence of this OUA-Na,K-ATPase signaling cascade in NMDA-mediated NF-κB activation. The findings presented here are the first report indicating that intrahippocampal administration of OUA, in a concentration that did not alter Na,K-ATPase or NOS activity, induced an activation of NF-κB, leading to increases in brain-derived neurotrophic factor (Bdnf), inducible NOS (iNos), tumor necrosis factor-α (Tnf-α), and B-cell leukemia/lymphoma 2 (Bcl2) mRNA levels. This response was not linked to any significant signs of neurodegeneration as showed via Fluoro-Jade B and Nissl stain. Intrahippocampal administration of NMDA induced NF-κB activation and increased NOS and α(2/3) -Na,K-ATPase activities. NMDA treatment further increased OUA-induced NF-κB activation, which was partially blocked by MK-801, an antagonist of NMDA receptor. These results suggest that OUA-induced NF-κB activation is at least in part dependent on Na,K-ATPase modulatory action of NMDA receptor in hippocampus. The interaction of these signaling pathways could be associated with biological mechanisms that may underlie the basal homeostatic state linked to the inflammatory signaling cascade in the brain.
authors: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors: E M
authors: EM
authors: Kawamoto
authors: L S
authors: LS
authors: Lima
authors: C D
authors: CD
authors: Munhoz
authors: L M
authors: LM
authors: Yshii
authors: P F
authors: PF
authors: Kinoshita
authors: F G
authors: FG
authors: Amara
authors: R R F
authors: RR
authors: Pestana
authors: A M M
authors: AM
authors: Orellana
authors: J
authors: J
authors: Cipolla-Neto
authors: L R G
authors: LR
authors: Britto
authors: M C W
authors: MC
authors: Avellar
authors: L V
authors: LV
authors: Rossoni
authors: C
authors: C
authors: Scavone
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016328:NF-kappa B; D009841:Oligonucleotides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D010042:Ouabain; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D052247:Nitric Oxide Synthase Type II; D000254:Sodium-Potassium-Exchanging ATPase