IKK mediates ischemia-induced neuronal death.
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.
Herrmann, O; Baumann, B; de Lorenzi, R; Muhammad, S; Zhang, W; Kleesiek, J; Malfertheiner, M; Köhrmann, M; Potrovita, I; Maegele, I; Beyer, C; Burke, JR; Hasan, MT; Bujard, H; Wirth, T; Pasparakis, M; Schwaninger, M
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