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The Journal of Neuroscience, July 1, 2001, 21(13):4668-4677
Activation of the Nuclear Factor- B Is a Key Event in
Brain Tolerance
Nicolas
Blondeau,
Catherine
Widmann,
Michel
Lazdunski, and
Catherine
Heurteaux
Institut de Pharmacologie Moléculaire et Cellulaire, Centre
National de la Recherche Scientifique, Unité Mixte de Recherche
6097, Sophia Antipolis, 06560 Valbonne, France
The transcription factor nuclear factor- B (NFB) is an
ubiquitously expressed inducible regulator of a broad range of genes and plays a pivotal role in cell death and survival pathways. Three
models of brain tolerance (ischemic, epileptic, and polyunsaturated fatty acid-induced preconditioning), known to confer resistance to
neurons against ischemia or status epilepticus, were used to determine
whether NFB mediated the late preconditioning. A sublethal 3 min
ischemia, a dose of 5 mg/kg kainic acid (KA5) or 500 nmol of linolenic
acid (LIN500) led to a rapid increase of NFB DNA-binding activity
and nuclear translocation of p65 and p50 subunits of NFB in neurons.
Pretreatment with the NFB inhibitor diethyldithiocarbamate or B
decoy DNA blocked the increased DNA-binding activity and the nuclear
translocation of NFB and abolished the neuroprotective effects of
different delayed preconditionings against severe ischemia or epilepsy.
The inhibition of NFB observed in rats preconditioned with 3 min
ischemia, KA5 or LIN500 treatments compared with ischemic or epileptic
controls was correlated with the prevention of the inducible
degradation of the inhibitory protein IB . Preconditioning probably inhibits the activation of NFB by interfering with a pathway that leads to the direct transcriptional activation of IB
by NFB itself. The present work provides evidence that activation of
NFB is a crucial step in the signal transduction pathway that underlies the development of brain tolerance and may open new strategies in the prevention of cerebral diseases, such as ischemia or epilepsy.
Key words:
NFB; brain preconditioning; ischemia; kainic acid; excitotoxicity; polyunsaturated fatty acids
Copyright © 2001 Society for Neuroscience 0270-6474/01/21134668-10$05.00/0
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