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

The transcription factor nuclear factor-kappaB (NF kappaB) is an ubiquitous ly expressed inducible regulator of a broad range of genes and plays a pivo tal role in cell death and survival pathways. Three models of brain toleran ce (ischemic, epileptic, and polyunsaturated fatty acid-induced preconditio ning), known to confer resistance to neurons against ischemia or status epi lepticus, were used to determine whether NF kappaB mediated the late precon ditioning. 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 diethyldith iocarbamate or kappaB decoy DNA blocked the increased DNA-binding activity and the nuclear translocation of NF kappaB and abolished the neuroprotectiv e 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 epilepti c 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 th e direct transcriptional activation of I kappaB alpha by NF kappaB itself. The present work provides evidence that activation of NF kappaB is a crucia l 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.