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-kappaB is well-known for its roles in preventing apoptotic cell death. Data indicated that NF-kappaB activation by pre-conditioning is part of a general brain tolerance program. Here we show that pre-conditioning leading to NF-kappaB activation also protects against oxidative insults generated by Fe2+ ions. Protection was accompanied by a long-lasting (more than 24 h) NF-kappaB 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-kappaB, which declined to basal levels after 24 h. Cell death was induced by hypericin at a concentration of 10 microM. A profound synergistic action in inducing apoptosis was detected in co-treatment of hypericin together with FeSO4. In contrast, hypericin in low concentrations was able to partly prevent cell death induced by amyloid-beta-peptide (Abeta). Hypericin (10 microM) synergistically enhanced Abeta 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-kappaB. Molecular inhibition of NF-kappaB activation with a transdominant negative IkappaB-alpha protected against staurosporine-induced cell death. In summary, the data describe NF-kappaB in the same primary neuronal culture as stimulus-dependent, anti-apoptotic, or pro-apoptotic factor.