IKK mediates ischemia-induced neuronal death

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

doi:10.1038/nm1323

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IKK mediates ischemia-induced neuronal death

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Hasan, Mazahir T.
Department of Biomedical Optics, Max Planck Institute for Medical Research, Max Planck Society;

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Herrmann, O., Baumann, B., de Lorenzi, R., Muhammad, S., Zhang, W., Kleesiek, J., et al. (2005). IKK mediates ischemia-induced neuronal death. Nature Medicine, 11(12), 1322-1329. doi:10.1038/nm1323.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002A-725B-7

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.