The nuclear factor-kappaB (NF-kappaB) family plays an important role in the control of the apoptotic response. Its activation has been demonstrated in both neurons and glial cells in many neurological disorders. In the present study, we specifically examined whether and to what extent NF-kappaB activation is involved in culture models of Parkinson's disease following exposure of MN9D dopaminergic neuronal cells to 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-4-phenylpyridinium ion (MPP+). Both analysis by immunocytochemistry and of immunoblots revealed that NF-kappaB-p65 was translocated into the nuclei following 6-OHDA but not MPP+-treatment. A time-dependent activation of NF-kappaB induced by 6-OHDA but not MPP+ was also demonstrated by an electrophoretic mobility shift assay. A competition assay indicated that not only NF-kappaB-p65 but also -p50 is involved in 6-OHDA-induced NF-kappaB activity. Co-treatment with an antioxidant, N-acetyl-L-cysteine, blocked 6-OHDA-induced activation of NF-kappaB signaling. In the presence of an NF-kappaB inhibitor, pyrrolidine dithiocarbarnate (PDTC), 6-OHDA-induced cell death was accelerated while PDTC did not affect MPP+-induced cell death. Our data may point to a drug-specific activation of NF-kappaB as a survival determinant for dopaminergic neurons. (C) 2004 Elsevier Inc. All rights reserved.