Stimulus-dependent activation of NF-κB specifies apoptosis or neuroprotection in cerebellar granule cells

Oxidative stress is believed to play an important role in neuronal cell death associated with several neurodegenerative diseases (e.g., Alzheimer disease, Parkinson disease, and cerebral ischemia). Neuronal cell death might be one of the crucial mediators of these diseases. The transcription factor NF-κB is well-known for its roles in preventing apoptotic cell death. Data indicated that NF-κB activation by pre-conditioning is part of a general brain tolerance program. Here we show that pre-conditioning leading to NF-κB activation also protects against oxidative insults generated by Fe^sup 2+^ ions. Protection was accompanied by a long-lasting (more than 24 h) NF-κB activation. Using this paradigm of oxidative insult, we analyzed the effect of hypericin, one of the active principles of St. John's Wort. Hypericin alone was able to induce short-time activation of NF-κB, which declined to basal levels after 24 h. Cell death was induced by hypericin at a concentration of 10 μM. A profound synergistic action in inducing apoptosis was detected in co-treatment of hypericin together with FeSO^sub 4^. In contrast, hypericin in low concentrations was able to partly prevent cell death induced by amyloid-β-peptide (Aβ). Hypericin (10 μM) synergistically enhanced Aβ neurotoxicity. Since hypericin is a described inhibitor of protein kinase C, we compared its action to staurosporine, another natural neuronal death-promoting PKC inhibitor. Staurosporine induced cell death and activates NF-κB. Molecular inhibition of NF-κB activation with a transdominant negative IκB-α protected against staurosporine-induced cell death. In summary, the data describe NF-κB in the same primary neuronal culture as stimulus-dependent, anti-apoptotic, or pro-apoptotic factor.