Published online before print February 26, 2004, doi: 10.1161/01.STR.0000120732.45951.26
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(Stroke. 2004;35:987.)
© 2004 American Heart Association, Inc.
Original Contributions |
Nuclear Factor-
B Contributes to Infarction After Permanent Focal Ischemia
From the A.I. Virtanen Institute, Department of Neurobiology, University of Kuopio, Kuopio, Finland (A.N., M.K., J.K); Department of Oncology, Kuopio University Hospital, Kuopio, Finland (J.K.); Departments of Neurology (P.J.L.) and Pathology (M.-L.K.-L.), Helsinki University Central Hospital, Helsinki, Finland; Neuroscience Program, Biomedicum, Helsinki, Finland (P.J.L.); Forschungszentrum Karlsruhe, Institute of Genetics, Karlsruhe, Germany (F.W.); and Division of Toxicology and Cancer Risk Factors, Cancer Research Center (N.F.), and Department of Neurology, University of Heidelberg, Heidelberg, Germany (W.Z., E.J., M.S.).
Reprint requests to Jari Koistinaho, MD, PhD, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, PO Box 1627, FIN-70211, Kuopio, Finland. E-mail jari.koistinaho{at}uku.fi
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 ß-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% (36.9±4.5 compared with 14.4±2.6; n=10; P<0.01) in the brain; this NF-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 mm3; n=12) smaller infarcts compared with wild-type controls (32.9±3.8 mm3; n=9; P<0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6±4.2 mm3; 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-B was activated in neurons in the penumbral areas.
Conclusions— NF-B is induced in neurons during human stroke, and activation of NF-B in the brain may contribute to infarction in pMCAO.
Key Words: knockout micecell culture • neuroprotective agents • inflammation • stroke • transcription factor • transgene • mice • rats
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