Differential alterations of NF-kappa B to oxidative stress in primary basal forebrain cultures

Oxidative stress has been linked to neuronal cell death resulting from eith er acute insults due to ischemia, trauma, excitotoxicity, or chronic neurod egenerative diseases. Cholinergic basal forebrain neurons (CBFNs) compete f or nerve growth factor (NGF) synthesized in the hippocampus and cortex via retrograde transport. NGF affects CBFN survival and cholinergic function vi a activation of the NF-kappa B transcription factor and this signaling path way appears to be impaired in aged rats. Here, we demonstrate that activati on of NF-kappa B in basal forebrain primary culture via treatment with hydr ogen peroxide or TNF-alpha is predominantly restricted to CBFNs, and that N F-kappa B activation appears to mostly affect p65 translocation to the nucl eus, but not the p50 subunit. These results are consistent with NF-kappa B activation being a part of recovery processes after acute oxidative stress. Since p50 or p49 (also called p52) binding to promoter sites does not stim ulate transcription - both p50 and p49 lack an activating domain - and p65 does contain an activating domain and thus can act as a transcription enhan cer, differential translocation of different NF-kappa B dimers can act as r epressors of constitutive activity or enhancers. These results are in agree ment with the hypothesis that p50/p65 is the active trans-activating specie s of NF-kappa B, as compared to p50/p50 homodimers which bind to NF-kappa B binding sites but do not trans-activate promoters. Our results also sugges t that selective activation of different NF-kappa B dimer species may have regulatory significance in neuronal responses to acute or chronic insults t o CNS. Thus, increased p65 translocation could have enhancing effects while increased p50 translocation could have a repressor role. Manipulation of t he types of NF-kappa B species being translocated could provide a basis for therapeutic strategies. (C) 2000 ISDN. Published by Elsevier Science Ltd. All rights reserved.