Differential alterations of NF-kappaB to oxidative stress in primary basal forebrain cultures.

Oxidative stress has been linked to neuronal cell death resulting from either acute insults due to ischemia, trauma, excitotoxicity, or chronic neurodegenerative diseases. Cholinergic basal forebrain neurons (CBFNs) compete for nerve growth factor (NGF) synthesized in the hippocampus and cortex via retrograde transport. NGF affects CBFN survival and cholinergic function via activation of the NF-kappaB transcription factor and this signaling pathway appears to be impaired in aged rats. Here, we demonstrate that activation of NF-kappaB in basal forebrain primary culture via treatment with hydrogen peroxide or TNF-alpha is predominantly restricted to CBFNs, and that NF-kappaB activation appears to mostly affect p65 translocation to the nucleus, but not the p50 subunit. These results are consistent with NF-kappaB activation being a part of recovery processes after acute oxidative stress. Since p50 or p49 (also called p52) binding to promoter sites does not stimulate transcription - both p50 and p49 lack an activating domain - and p65 does contain an activating domain and thus can act as a transcription enhancer, differential translocation of different NF-kappaB dimers can act as repressors of constitutive activity or enhancers. These results are in agreement with the hypothesis that p50/p65 is the active trans-activating species of NF-kappaB, as compared to p50/p50 homodimers which bind to NF-kappaB binding sites but do not trans-activate promoters. Our results also suggest that selective activation of different NF-kappaB dimer species may have regulatory significance in neuronal responses to acute or chronic insults to CNS. Thus, increased p65 translocation could have enhancing effects while increased p50 translocation could have a repressor role. Manipulation of the types of NF-kappaB species being translocated could provide a basis for therapeutic strategies.