IKK mediates ischemia-induced neuronal death

  title={IKK mediates ischemia-induced neuronal death},
  author={Oliver Herrmann and Bernd Baumann and Rossana de Lorenzi and Sajjad Muhammad and Wen Zhang and Jens Kleesiek and Maximillian V. Malfertheiner and Martin Köhrmann and Ioana Potrovita and Ira Maegele and Cordian Beyer and James R Burke and Mazahir T. Hasan and Hermann Prof. Dr. Bujard and Thomas Wirth and Manolis Pasparakis and Markus Schwaninger},
  journal={Nature Medicine},
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… 
NF-κB signalling in cerebral ischaemia
There is evidence that IKK/NF-kappaB signalling contributes to ischaemic brain damage and may provide suitable drug targets for the treatment of stroke.
Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia
This study demonstrates that TAK1 is a central target for short-term inhibition of key signaling pathways and neuroprotection in cerebral ischemia and upregulated another MAP3K, apoptosis signal-regulating kinase-1, which is able to compensate for TAK 1 inhibition.
Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage.
NF-κB regulates the outcome of transient forebrain ischemia in middle-aged subjects in a sex-specific way, having an impact not only on neuronal death but also specific inflammatory responses and neurogenesis.
Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia
The deleterious function in cerebral ischemia is specific for the NF-κB subunit RelA and may be mediated through Bim and Noxa, and expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genes Bim-Noxa in cerebral waschemia depended onrelA and the upstream kinase IKK (IκB kinase).
p53-mediated neuronal cell death in ischemic brain injury
In various stroke models, p53 deficiency or applications of p53 inhibitors can significantly attenuate brain damage and has become a therapeutic target against stroke pathology.
Oxidative Stress Increases Phosphorylation of IκB Kinase-α by Enhancing NF-κB-Inducing Kinase after Transient Focal Cerebral Ischemia
  • Y. Song, Min-Soo Kim, P. Chan
  • Biology, Chemistry
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2010
The results suggest that augmentation of NIK, IKKα, and pH3 in response to oxidative stress is involved in cell death after cerebral ischemia (or stroke).
IKK2/NF-κB signaling protects neurons after traumatic brain injury
  • M. Mettang, S. Reichel, T. Wirth
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2018
This study demonstrates that physiological neuronal IKK/NF‐κB signaling is necessary and sufficient to protect neurons from trauma consequences and identifies elevated levels of the proapoptotic mediators Bax and Bad and enhanced expression of stress response genes.


Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury.
AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.
Neuronal Activation of NF-κB Contributes to Cell Death in Cerebral Ischemia
The data show that NF-κB is activated in neurons and astrocytes during cerebral ischemia and that NF -κB activation in neurons contributes to the ischemic damage.
Activation of the IκB Kinase Complex and Nuclear Factor-κB Contributes to Mutant Huntingtin Neurotoxicity
In acute striatal slice cultures, blocking degradation of NF-κB inhibitors with a dominant-negative ubiquitin ligase β-transducin repeat-containing protein also reduces the toxicity of mutant Htt in MSNs.
NF-κB is activated and promotes cell death in focal cerebral ischemia
In p50 knockout mice, ischemic damage was significantly reduced and indicates a cell death-promoting role of NF-κB in focal ischemia, which may provide a new pharmacological target in neurologic disease.
Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice
Results suggest that ROS are implicated in transient downregulation of IKKα, β, and γ in cerebral ischemia.
IκB Kinase Is an Essential Component of the Tpl2 Signaling Pathway
It is shown that IκB kinase serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK, and that IKKβ exerts its immune-regulatory functions by targeting different downstream signaling pathways.
Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity.
In acute striatal slice cultures, inhibition of IKK activity with an N-terminally truncated form of Ikkgamma blocks mutant Htt-induced toxicity in medium-sized spiny neurons (MSNs), and blocking degradation of NF-kappaB inhibitors with a dominant-negative ubiquitin ligase beta-transducin repeat-containing protein also reduces the toxicity of mutant HTT in MSNs.
Glutamate activates NF-kappaB through calpain in neurons.
The data indicate that the Ca2+-dependent protease calpain is involved in the NF-kappaB activation in neurons in response to N-methyl-d-aspartate receptor occupancy by glutamate, and may mediate the long-term effects of glutamate on neuron survival or memory formation.
Mild Hypothermia Inhibits Nuclear Factor-κB Translocation in Experimental Stroke
The data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFκB inhibition due to decreased activity of IKK, and this may be related to inducible nitric oxide synthase and TNF-α.
IkappaB kinase is an essential component of the Tpl2 signaling pathway.
Inhibition of IKKbeta in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha, and suggest that IKK beta exerts its immune-regulatory functions by targeting different downstream signaling pathways.