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.

Background and Purpose-Activation of transcription factor nuclear factor-B (NF-B) may induce expression of either proinflammatory/apoptotic genes or antiapoptotic genes. Because a considerable number of middle cerebral artery occlusions (MCAOs) in humans are not associated with reperfusion during the first 24 hours, the role of NF-B after permanent MCAO (pMCAO) was investigated. Methods-Mice transgenic for a NF-B-driven ␤-globin reporter were exposed to pMCAO, and the expression of the reporter gene was quantified with real-time polymerase chain reaction. Mice lacking the p50 subunit of NF-B and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate (PDTC), an NF-B inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-B. Results-pMCAO increased NF-B transcriptional activity to 260% (36.9Ϯ4.5 compared with 14.4Ϯ2.6; nϭ10; PϽ0.01) in the brain; this NF-B activation was completely blocked by PDTC (17.2Ϯ2.6; nϭ9; PϽ0.05). In p50 Ϫ/Ϫ mice, pMCAO resulted in 41% (18Ϯ3.2 mm 3 ; nϭ12) smaller infarcts compared with wild-type controls (32.9Ϯ3.8 mm 3 ; nϭ9; PϽ0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6Ϯ4.2 mm 3 ; nϭ8). Pro-DTC, a PDTC analogue that does not cross the blood-brain barrier, had no effect, even though Pro-DTC and PDTC were equally protective in vitro. During the first 2 days of human stroke, NF-B was activated in neurons in the penumbral areas. Conclusions-NF-B is induced in neurons during