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.
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Acknowledgements
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.
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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.
Supplementary information
Supplementary Fig. 1
Nissl staining of coronal brain sections showed no gross anatomical differences between IKK2nKO and control mice. (PDF 203 kb)
Supplementary Fig. 2
Immunohistochemistry of IKK1/2 in sagittal brain slices of IKK2nDN animals. (PDF 277 kb)
Supplementary Fig. 3
Luciferase activity was measured in brain regions identical to Figure 3c. (PDF 78 kb)
Supplementary Fig. 4
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)
Supplementary Fig. 5
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)
Supplementary Table 1
Physiological parameters of IKK2CNSKO mice and control mice. (PDF 23 kb)
Supplementary Table 2
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). https://doi.org/10.1038/nm1323
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DOI: https://doi.org/10.1038/nm1323
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