Published Online
on February 26, 2004

A more recent version of this article appeared on April 1, 2004

This Article Full Text (PDF) All Versions of this Article: 35/4/987    most recent 01.STR.0000120732.45951.26v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nurmi, A. Articles by Koistinaho, J. Search for Related Content PubMed PubMed Citation Articles by Nurmi, A. Articles by Koistinaho, J. Related Collections Carotid Stenosis Doppler ultrasound, Transcranial Doppler etc.

Submitted on December 15, 2003
Accepted on December 29, 2003

Nuclear Factor-B Contributes to Infarction After Permanent Focal Ischemia

Antti Nurmi MSc; Perttu J. Lindsberg MD, PhD; Milla Koistinaho PhD; Wen Zhang MD; Eric Juettler MD; Marja-Liisa Karjalainen-Lindsberg MD, PhD; Falk Weih PhD; Norbert Frank PhD; Markus Schwaninger MD; and Jari Koistinaho MD, PhD^*

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.).

^* To whom correspondence should be addressed. 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 -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 mice • cell culture • neuroprotective agents • inflammation • stroke • transcription factor • transgene • mice • rats

This article has been cited by other articles:

				A. Kunz, T. Abe, K. Hochrainer, M. Shimamura, J. Anrather, G. Racchumi, P. Zhou, and C. Iadecola Nuclear Factor-{kappa}B Activation and Postischemic Inflammation Are Suppressed in CD36-Null Mice after Middle Cerebral Artery Occlusion J. Neurosci., February 13, 2008; 28(7): 1649 - 1658. [Abstract] [Full Text] [PDF]

				X. Zhang, R. Polavarapu, H. She, Z. Mao, and M. Yepes Tissue-Type Plasminogen Activator and the Low-Density Lipoprotein Receptor-Related Protein Mediate Cerebral Ischemia-Induced Nuclear Factor-{kappa}B Pathway Activation Am. J. Pathol., October 1, 2007; 171(4): 1281 - 1290. [Abstract] [Full Text] [PDF]

				O. Baranova, L. F. Miranda, P. Pichiule, I. Dragatsis, R. S. Johnson, and J. C. Chavez Neuron-Specific Inactivation of the Hypoxia Inducible Factor 1{alpha} Increases Brain Injury in a Mouse Model of Transient Focal Cerebral Ischemia J. Neurosci., June 6, 2007; 27(23): 6320 - 6332. [Abstract] [Full Text] [PDF]

				T. Ahtoniemi, G. Goldsteins, V. Keksa-Goldsteine, T. Malm, K. Kanninen, A. Salminen, and J. Koistinaho Pyrrolidine Dithiocarbamate Inhibits Induction of Immunoproteasome and Decreases Survival in a Rat Model of Amyotrophic Lateral Sclerosis Mol. Pharmacol., January 1, 2007; 71(1): 30 - 37. [Abstract] [Full Text] [PDF]

				I. Inta, S. Paxian, I. Maegele, W. Zhang, M. Pizzi, P. Spano, I. Sarnico, S. Muhammad, O. Herrmann, D. Inta, et al. Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-{kappa}B Subunit RelA in Cerebral Ischemia J. Neurosci., December 13, 2006; 26(50): 12896 - 12903. [Abstract] [Full Text] [PDF]

				S.-K. Jo, G. J. Ko, C. S. Boo, W. Y. Cho, and H. K. Kim Heat Preconditioning Attenuates Renal Injury in Ischemic ARF in Rats: Role of Heat-Shock Protein 70 on NF-{kappa}B-Mediated Inflammation and on Tubular Cell Injury J. Am. Soc. Nephrol., November 1, 2006; 17(11): 3082 - 3092. [Abstract] [Full Text] [PDF]

				P. J. Crack, J. M. Taylor, U. Ali, A. Mansell, and P. J. Hertzog Potential Contribution of NF-{kappa}B in Neuronal Cell Death in the Glutathione Peroxidase-1 Knockout Mouse in Response to Ischemia-Reperfusion Injury Stroke, June 1, 2006; 37(6): 1533 - 1538. [Abstract] [Full Text] [PDF]

				S. F. Liu and A. B. Malik NF-{kappa}B activation as a pathological mechanism of septic shock and inflammation Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L622 - L645. [Abstract] [Full Text] [PDF]

				R. Garg, A. Chaudhuri, F. Munschauer, and P. Dandona Hyperglycemia, Insulin, and Acute Ischemic Stroke: A Mechanistic Justification for a Trial of Insulin Infusion Therapy Stroke, January 1, 2006; 37(1): 267 - 273. [Abstract] [Full Text] [PDF]

				X. Wei, L. Zhao, Z. Ma, D. M. Holtzman, C. Yan, R. C. Dodel, H. Hampel, W. Oertel, M. R. Farlow, and Y. Du Caffeic acid phenethyl ester prevents neonatal hypoxic-ischaemic brain injury Brain, December 1, 2004; 127(12): 2629 - 2635. [Abstract] [Full Text] [PDF]