![]() ![]() Noxious stimuli applied at doses close to but below the threshold of cell injury induce adaptative responses that protect the brain against additional stress from the same (tolerance) or other (cross-tolerance) stimuli. The present work provides evidence that activation of NFκB 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. Preconditioning probably inhibits the activation of NFκB by interfering with a pathway that leads to the direct transcriptional activation of IκBα by NFκB itself. The inhibition of NFκB 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 IκBα. Pretreatment with the NFκB inhibitor diethyldithiocarbamate or κB decoy DNA blocked the increased DNA-binding activity and the nuclear translocation of NFκB and abolished the neuroprotective effects of different delayed preconditionings against severe ischemia or epilepsy. 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 NFκB DNA-binding activity and nuclear translocation of p65 and p50 subunits of NFκB in neurons. ![]() 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 NFκB mediated the late preconditioning. The transcription factor nuclear factor-κB (NFκB) is an ubiquitously expressed inducible regulator of a broad range of genes and plays a pivotal role in cell death and survival pathways. ![]()
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