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.
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This study was supported by Deutsche Forschungsgemeinschaft grants SCHW 416/4-2 (to M.S.) and SFB 497/B1 (to B.B.), Bundesministerium für Bildung und Forschung grant NGFN2 (to M.S.), and European Union grant QLG1-CT-1999-00202 (to M.P.). We thank H. Schröck (Heidelberg) for help with physiological parameters, R. Kühn (Neuherberg, Germany) for providing CamKII-Cre mice, R. Klein (Munich) for providing Nestin-Cre mice and Y. Qiu (Bristol-Myers Squibb) for his work toward synthesis of BMS-345541.
James R. Burke is employed by Bristol-Meyers Squibb. Bristol-Meyers Squibb is interested in the development and commercialization of IKK2 inhibitors as therapeutics for the treatment of stroke.
Nissl staining of coronal brain sections showed no gross anatomical differences between IKK2nKO and control mice. (PDF 203 kb)
Immunohistochemistry of IKK1/2 in sagittal brain slices of IKK2nDN animals. (PDF 277 kb)
Luciferase activity was measured in brain regions identical to Figure 3c. (PDF 78 kb)
Junb expression in IKK2nCA mice and littermate controls was determined by semi-quantitative RT-PCR in brain regions identical to Figure 4. (PDF 54 kb)
Induction of the proapoptotic genes Fas and Myc and of the antiapoptotic genes Birc3, Bdnf, Epo and Csf3 by MCAO was not inhibited by BMS-345541 treatment. (PDF 80 kb)
Physiological parameters of IKK2CNSKO mice and control mice. (PDF 23 kb)
Physiological parameteres of C57Bl/6 mice 20 min after intracerebroventricular injection of 2 μl saline or 20 mM BMS-345541 and 15 min after MCAO. (PDF 19 kb)
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Herrmann, O., Baumann, B., de Lorenzi, R. et al. IKK mediates ischemia-induced neuronal death. Nat Med 11, 1322–1329 (2005) doi:10.1038/nm1323
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