Consistent with a previous report, we found that ATF4 was upregulated by 6-OHDA, both translationally and transcriptionally, in PC12 cells. Addition of luteolin significantly attenuated ATF4 expression at both stages. Under ER stress, cells activate GRP78, which protects them from lethal conditions, and CHOP, which plays major roles in ER stress induced apoptosis. We observed that 6-OHDA induced the expression of GRP78 and CHOP in PC12 cells. Because UPR mediated cell survival or death is regulated by the balance of GRP78 and CHOP expression, the preferential induction of CHOP rather than GRP78 in PC12 cells exposed to 6-OHDA indicates the possible involvement of ER stress in its cytotoxicity. Furthermore, in parallel to the protective effects, luteolin attenuated 6-OHDA-mediated expression of CHOP more effectively than GRP78. The Nrf2-ARE transcriptional pathway plays an important role in the regulation of genes that control the expression of proteins critical in the detoxication and Lithocholic acid elimination of ROS and electrophiles. Quinone electrophiles are indirect inhibitors of the Keap1-Nrf2 interaction, and are believed to form covalent adducts with the sulfhydryl groups of cysteines in Keap1 by oxidation or alkylation. Furthermore, direct covalent modification of Nrf2 by phosphorylation/dephosphorylation and acetylation/deacetylation affects nuclear translocation/export, and transcription activation, and degradation of Nrf2 has been reported in response to oxidative stress and toxicity. Upon ER stress, PERK phosphorylates Nrf2, resulting in dissociation of the Nrf2-Keap1 complex, nuclear localization of Nrf2 and activation of transcription by Nrf2 through the antioxidant response element. In this study, we found that 6-OHDA induces modest increases in mRNA expression of Nrf2 and GCLC, and dramatic rise in HO-1 expression. Nrf2 siRNA partially decreased HO-1 expression, indicating Nrf2 and other transcription factors might be involved in this process. A growing body of evidence shows the hormetic actions of Nrf2 and HO-1. Although Nrf2 activation protects Malotilate against acute toxicity and prevents or attenuates several disease states, constitutive activation leads to poor clinical outcomes.