Activation of the nuclear factor-κB is a key event in brain tolerance

The transcription factor nuclear factor-kappaB (NF kappaB) 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 NF kappaB 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 NF kappaB DNA-binding activity and nuclear translocation of p65 and p50 subunits of NF kappaB in neurons. Pretreatment with the NF kappaB inhibitor diethyldithiocarbamate or kappaB decoy DNA blocked the increased DNA-binding activity and the nuclear translocation of NF kappaB and abolished the neuroprotective effects of different delayed preconditionings against severe ischemia or epilepsy. The inhibition of NF kappaB 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 I kappaB alpha. Preconditioning probably inhibits the activation of NF kappaB by interfering with a pathway that leads to the direct transcriptional activation of I kappaB alpha by NF kappaB itself. The present work provides evidence that activation of NF kappaB 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.