In acute stroke, neuronal apoptosis and inflammation are considered to be important mechanisms on the road to tissue loss and neurological deficit. Both apoptosis and inflammation depend on gene transcription. We have identified a signalling pathway that regulates transcription of genes involved in apoptosis and inflammation. In a mouse model of focal cerebral ischaemia, there is an induction of the cytokine TWEAK (tumour necrosis factor-like weak inducer of apoptosis) and its membrane receptor Fn14. TWEAK promotes neuronal cell death and activates the transcription factor NF-κB (nuclear factor κB) through the upstream kinase IKK [IκB (inhibitory κB) kinase]. In vivo, IKK is activated in neurons. Neuron-specific deletion of the subunit IKK2 or inhibition of IKK activity reduced the infarct size and neuronal cell loss. A pharmacological inhibitor of IKK also showed neuroprotective properties. IKK-dependent ischaemic brain damage is likely to be mediated by NF-κB, because neuron-specific inhibition of NF-κB through transgenic expression of the NF-κB superrepressor was found to reduce the infarct size. In summary, there is evidence that IKK/NF-κB signalling contributes to ischaemic brain damage and may provide suitable drug targets for the treatment of stroke.
Conference Article| October 25 2006
NF-κB signalling in cerebral ischaemia
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M. Schwaninger, I. Inta, O. Herrmann; NF-κB signalling in cerebral ischaemia. Biochem Soc Trans 1 December 2006; 34 (6): 1291–1294. doi: https://doi.org/10.1042/BST0341291
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