NF-kappa B mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH-EP1 through JNK and c-Jun/AP-1

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra with unknown etiology. Neuropathology seen in the brains of PD patients can be closely mimicked by MPP+-induced neurotoxicity in vitro. In this study, we used an S-type human neuroblastoma cell line (SH-EP1) as a model to investigate the involvement of NF-kappa B and JNK pathways in MPP+-induced neurotoxicity. We show that NF-kappa B was activated by MPP+ as evidenced by NF-kappa B p65 nuclear translocation, the increased DNA binding activity and a rapid phosphorylation of NF-kappa B inhibitor (I kappa B alpha). NF-kappa B partially mediated the neurotoxicity of MPP+, as Suggested by the reduction of MPP+-induced cell death by both a specific I kappa B kinase (IKK) inhibitor and a dominant negative form of I kappa B alpha (I kappa B alpha-M). Besides NF-kappa B, JNK and c-Jun/AP-1 were also activated upon MPP+ stimulation. Inhibition of JNK activation with a specific JNK inhibitor partially reduced the MPP+-mediated cell death. Similarly, inhibition of c-Jun/AP-1 activation, either by a dominant negative c-Jun or c-Jun/AP-1 inhibitor, significantly attenuated MPP+-mediated cell death. These results suggest that both JNK and c-Jun/AP-1 activation are pro-apoptotic. Furthermore, we provide clear evidence for the existence of a crosstalk between the NF-kappa B and JNK signaling as MPP+-induced activation of JNK and c-Jun/AP-1 was strongly down-regulated in I kappa B alpha-M cells. In conclusion, we demonstrate that in SH-EP1 cells MPP+-induced neurotoxicity is partially mediated by NF-kappa B which in turn acts on the activation of JNK and c-Jun/AP-1. These results may point to a combined inhibition of NF-kappa B and JNK as a new approach to PD therapy. (C) 2009 Elsevier Ltd. All rights reserved.