title: Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia.
abstract: The transcription factor NF-kappaB is a key regulator of inflammation and cell survival. NF-kappaB is activated by cerebral ischemia in neurons and glia, but its function is controversial. To inhibit NF-kappaB selectively in neurons and glial cells, we have generated transgenic mice that express the IkappaBalpha superrepressor (IkappaBalpha mutated at serine-32 and serine-36, IkappaBalpha-SR) under transcriptional control of the neuron-specific enolase (NSE) and the glial fibrillary acidic protein (GFAP) promoter, respectively. In primary cortical neurons of NSE-IkappaBalpha-SR mice, NF-kappaB activity was partially inhibited. To assess NF-kappaB activity in vivo after permanent middle cerebral artery occlusion (MCAO), we measured the expression of NF-kappaB target genes by real-time polymerase chain reaction (PCR). The induction of c-myc and transforming growth factor-beta2 by cerebral ischemia was inhibited by neuronal expression of IkappaBalpha-SR, whereas induction of GFAP by MCAO was reduced by astrocytic expression of IkappaBalpha-SR. Neuronal, but not astrocytic, expression of the NF-kappaB inhibitor reduced both infarct size and cell death 48 hours after permanent MCAO. In summary, the data show that NF-kappaB is activated in neurons and astrocytes during cerebral ischemia and that NF-kappaB activation in neurons contributes to the ischemic damage.
authors.affiliation: Department of Neurology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Ioana
authors.initials: I
authors.lastname: Potrovita
authors.forename: Victoria
authors.initials: V
authors.lastname: Tarabin
authors.forename: Oliver
authors.initials: O
authors.lastname: Herrmann
authors.forename: Verena
authors.initials: V
authors.lastname: Beer
authors.forename: Falk
authors.initials: F
authors.lastname: Weih
authors.forename: Armin
authors.initials: A
authors.lastname: Schneider
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D020672:I-kappa B Proteins; C489428:Myc protein, mouse; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D000072000:NF-KappaB Inhibitor alpha; D010751:Phosphopyruvate Hydratase