Luteolin has multiple bioactivities and neuroprotective effects, exhibits anti-inflammatory activity in microglia and attenuates neuro toxicities induced by peroxide, amyloid b protein and 6-OHDA in cell culture. Luteolin can cross the blood-brain Dynasore barrier and has anti-amnesic effects against the toxicity of Ab in mice while attenuating scopolamine-induced amnesia in rats. Nevertheless, the molecular mechanism underlying its neuroprotective activity against 6-OHDA-induced cytotoxicity remains unclear. The specific aim of this study is thus to investigate how luteolin affects 6-OHDA-stimulated cellular stress responses, namely, the p53, ER-UPR and Nrf2-ARE pathways, in PC12 cells, and the results may provide valuable insights into the mechanisms underlying its neuroprotective effects. Previous research has demonstrated that the addition of catalase, an H2O2-removing enzyme, completely abolished the cytotoxic effect of H2O2, while a significant but partial protective effect was observed against that of 6-OHDA. In the current study we examined the effects of two other ROS scavengers, tiron and a-lipoic acid. Tiron is a cellular permeable superoxide scavenger, and high concentration of tiron has been shown to partially prevent 6-OHDA-induced PC12 cell death. a-lipoic acid is a direct scavenger of ROS/RNS in vitro, and an effector of important cellular stress response pathways that ultimately influence endogenous cellular antioxidant levels and reduce proinflammatory mechanisms, while also Batimastat serving as a potential alternative therapy for PD. We found that the thiol reductive agent LA did not change intracellular ROS level or protect PC12 cells from 6-OHDA-induced cytotoxicity. On the other hand, tiron inhibited 6-OHDA-mediated ROS production in PC12 cells in a dose-dependent manner, but only 5 mM tiron exhibited a cytoprotective effect. The fact that complete depletion of ROS by tiron only partially restored cell viability supports the earlier notion that, in addition to oxidative stress, 6-OHDAinduced cell death may result from other pathways. Furthermore, the higher efficacy of luteolin may be attributed not only to its direct ROS scavenging activity, but also to modulating other signaling pathways.