6-Hydroxydopamine (6-OHDA) is widely used to study the death of catecholaminergic cells related to Parkinson's disease. Oxidative stress and gene transcription are known to mediate the pro-apoptotic effect of 6-OHDA. As redox mechanisms are involved in activation of the transcription factor NF-kappaB, we studied the role of NF-kappaB in 6-OHDA-induced death of PC12 cells. We stably transfected PC12 cells with a doxycycline-regulated expression vector for the NF-kappaB super-repressor (IkappaBalpha mutated at serine-32 and serine-36, IkappaBalpha-SR). NF-kappaB transcriptional activity was evaluated by transient transfection of an NF-kappaB-driven luciferase reporter gene. Expression of IkappaBalpha-SR inhibited NF-kappaB stimulated by tumor necrosis factor alpha (TNFalpha) and 6-OHDA. Apoptosis was quantified by counting cells with condensed nuclei. IkappaBalpha-SR inhibited apoptosis induced by 6-OHDA but enhanced apoptosis that was triggered by TNFalpha. The converse effects of NF-kappaB could be due to different target genes that are induced in the context of TNFalpha and 6-OHDA stimulation. Indeed, TNFalpha stimulated mRNA accumulation of the anti-apoptotic superoxide dismutase 2 through NF-kappaB whereas 6-OHDA induced mRNA accumulation of the pro-apoptotic c-myc. These data demonstrate that NF-kappaB regulates survival of the neuron-like PC12 cells in a stimulus-specific manner. In the context of 6-OHDA stimulation, NF-kappaB mediates pro-apoptotic effects, suggesting that NF-kappaB signaling could be a target for drug development in Parkinson-related neurodegeneration.