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
Oliver
O
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Baumann
Bernd
B
de Lorenzi
Rossana
R
Muhammad
Sajjad
S
Zhang
Wen
W
Kleesiek
Jens
J
Malfertheiner
Max
M
Köhrmann
Martin
M
Potrovita
Ioana
I
Maegele
Ira
I
Beyer
Cordian
C
Burke
James R
JR
Hasan
Mazahir T
MT
Bujard
Hermann
H
Wirth
Thomas
T
Pasparakis
Manolis
M
Schwaninger
Markus
M
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D047569:Laser Scanning Cytometry; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D007093:Imidazoles; D011810:Quinoxalines; D051550:I-kappa B Kinase