Neuronal Activation of NF-κB Contributes to Cell Death in Cerebral Ischemia:

The transcription factor NF-jB is a key regulator of inflammation and cell survival. NF-jB is activated by cerebral ischemia in neurons and glia, but its function is controversial. To inhibit NF-jB selectively in neurons and glial cells, we have generated transgenic mice that express the IjBa superrepressor (IjBa mutated at serine-32 and serine-36, IjBa-SR) under transcriptional control of the neuron-specific enolase (NSE) and the glial fibrillary acidic protein (GFAP) promoter, respectively. In primary cortical neurons of NSE-IjBa-SR mice, NF-jB activity was partially inhibited. To assess NF-jB activity in vivo after permanent middle cerebral artery occlusion (MCAO), we measured the expression of NF-jB target genes by real-time polymerase chain reaction (PCR). The induction of c-myc and transforming growth factor-b2 by cerebral ischemia was inhibited by neuronal expression of IjBa-SR, whereas induction of GFAP by MCAO was reduced by astrocytic expression of IjBa-SR. Neuronal, but not astrocytic, expression of the NF-jB inhibitor reduced both infarct size and cell death 48 hours after permanent MCAO. In summary, the data show that NF-j Bi s activated in neurons and astrocytes during cerebral ischemia and that NF-jB activation in neurons contributes to the ischemic damage.