It has been reported that Nrf2 activation and subsequent induction of HO-1 mediate the cellular adaptive survival response to 6-OHDA-induced cell death. On the other hand, sustained HO-1 over-expression contributes to the iron sequestration, intracellular oxidative stress and mitochondrial damage documented in aging-related neurodegenerative disorders, such as Alzheimer��s disease and PD. Therefore, 6OHDA-induced expression and possible activation of Nrf2 may be harmful rather than protective for PC12 cells in this study. We previously reported that Domiphen Bromide luteolin itself is a mild ARE inducer, Carbimazole induces moderate HO-1 expression in PC12 cells, and exerts cytoprotective effects. However, in the current work we found that addition of luteolin and tiron inhibited 6-OHDA-mediated HO-1 and GCLC mRNA expression, and this might be associated with their detoxifying effects. This indicates that 6-OHDAmediated ROS production is involved in Nrf2-mediated gene expression, and that the preconditioning effects induced by luteolin mediate an adaptive response to 6-OHDA-induced cytotoxicity. The pro-apoptotic activity of BH3-only proteins can be regulated by a variety of transcriptional and posttranslational control mechanisms. BIM, a pro-apoptotic BH3-only member of the Bcl-2 family, is required for initiation of apoptosis induced by ER stress. TRB3 expression is upregulated in a variety of cell types under various stress conditions, including ER stress, nutrient deprivation, hypoxia and oxidative stress and is a critical molecule in apoptosis. We found that 6-OHDA stimulated the mRNA expression of BIM and TRB3, and both of these can be completely blocked by luteolin. The growth arrest and DNA damage-inducible protein, GADD34, forms a complex with the protein phosphatase 1 to dephosphorylate eIF2a, and promotes protein translation in mammalian cells. Consistent with a previous report that PC12 cells treated with 6-OHDA caused an increase in the transcription of GADD34, addition of luteolin significantly decreased its induction, but did not completely prevent it. In conclusion, we found that 6-OHDA induces transcription of genes involved in the p53, Nrf2-ARE and eIF2a-ATF4-CHOP pathways, and these subsequently cause pro-apoptotic gene overexpression and caspase-3 activation.