Nuclear factor-κB contributes to infarction after permanent focal ischemia

被引:298
作者
Nurmi, A
Lindsberg, PJ
Koistinaho, M
Zhang, W
Juettler, E
Karjalainen-Lindsberg, ML
Weih, F
Frank, N
Schwaninger, M
Koistinaho, J
机构
[1] Univ Kuopio, AI Virtanen Inst Mol Sci, Dept Neurobiol, FIN-70211 Kuopio, Finland
[2] Kuopio Univ Hosp, Dept Oncol, SF-70210 Kuopio, Finland
[3] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland
[4] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland
[5] Biomedicum, Neurosci Program, Helsinki, Finland
[6] Forschungszentrum Karlsruhe, Inst Genet, D-76021 Karlsruhe, Germany
[7] German Canc Res Ctr, Div Toxicol & Canc Risk Factors, D-6900 Heidelberg, Germany
[8] Heidelberg Univ, Dept Neurol, Heidelberg, Germany
关键词
knockout mice; cell culture; neuroprotective agents; inflammation; stroke; transcription factor; transgene; mice; rats;
D O I
10.1161/01.STR.0000120732.45951.26
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and Purpose-Activation of transcription factor nuclear factor-kappaB (NF-kappaB) 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-kappaB after permanent MCAO (pMCAO) was investigated. Methods-Mice transgenic for a NF-kappaB-driven beta-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-kappaB and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate ( PDTC), an NF-kappaB inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-kappaB. Results-pMCAO increased NF-kappaB transcriptional activity to 260% (36.9+/-4.5 compared with 14.4+/-2.6; n=10; P<0.01) in the brain; this NF-kappa B activation was completely blocked by PDTC (17.2 +/- 2.6; n=9; P<0.05). In p50(-/-) mice, pMCAO resulted in 41% (18+/-3.2 mm(3); n=12) smaller infarcts compared with wild-type controls (32.9+/-3.8 mm(3); n=9; P<0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6 +/- 4.2 mm(3); n=8). 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-kappa B was activated in neurons in the penumbral areas. Conclusions-NF-kappa B is induced in neurons during human stroke, and activation of NF-kappa B in the brain may contribute to infarction in pMCAO.
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收藏
页码:987 / 991
页数:5
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