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 language | English |
|---|---|
| Journal | Nature Medicine |
| Volume | 11 |
| Issue number | 12 |
| Pages (from-to) | 1322-1329 |
| Number of pages | 8 |
| ISSN | 1078-8956 |
| DOIs | |
| Publication status | Published - 01.12.2005 |
Funding
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,
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
