title: IKK mediates ischemia-induced neuronal death.
abstract: The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.
authors.affiliation: Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Herrmann
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
authors.forename: Rossana
authors.initials: R
authors.lastname: de Lorenzi
authors.forename: Sajjad
authors.initials: S
authors.lastname: Muhammad
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Jens
authors.initials: J
authors.lastname: Kleesiek
authors.forename: Max
authors.initials: M
authors.lastname: Malfertheiner
authors.forename: Martin
authors.initials: M
authors.lastname: Köhrmann
authors.forename: Ioana
authors.initials: I
authors.lastname: Potrovita
authors.forename: Ira
authors.initials: I
authors.lastname: Maegele
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
authors.forename: James R
authors.initials: JR
authors.lastname: Burke
authors.forename: Mazahir T
authors.initials: MT
authors.lastname: Hasan
authors.forename: Hermann
authors.initials: H
authors.lastname: Bujard
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D047569:Laser Scanning Cytometry; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D007093:Imidazoles; D011810:Quinoxalines; D051550:I-kappa B Kinase