IKK mediates ischemia-induced neuronal death

Oliver Herrmann, Bernd Baumann, Rossana De Lorenzi, Sajjad Muhammad, Wen Zhang, Jens Kleesiek, Max Malfertheiner, Martin Köhrmann, Ioana Potrovita, Ira Maegele, Cordian Beyer, James R. Burke, Mazahir T. Hasan, Hermann Bujard, Thomas Wirth, Manolis Pasparakis, Markus Schwaninger

Research output: Contribution to journalArticlepeer-review

232 Scopus citations

Abstract

The IκB kinase complex IKK is a central component of the signaling cascade that controls NF-κB-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.

Original languageEnglish
Pages (from-to)1322-1329
Number of pages8
JournalNature Medicine
Volume11
Issue number12
DOIs
StatePublished - Dec 2005
Externally publishedYes

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