Background: Oxidative stress is considered to have a causative role in the development of central nervous system diseases, such as Alzheimers disease, Parkinsons disease, tumor, etc.Curcumin, a polyphenol extracted from rhizomes of the plant Curcuma Longa, is widely reported to have a diversity of anti-oxidative stress, but the underlying mechanism has not been fully elucidated.We investigated the mechanism of the neuroprotective properties of curcumin in human neuroblastoma SH-SY5Y cells subjected to oxidative stress.Methods: The cells were treated with curcurnin at different concentration (1.25, 5, 20 μM) for 24, 48, 72 h and/or with PI3k inhibitor LY294002 or Nrf-2 siRNA, the protection of curcumin against H202-induced toxicity was measured as ROS production and reduced cell growth.RT-PCR and Westemblot were applied for detecting the expression of HO-1, HO-2, PI3kK, Akt and Nrf-2 at mRNA and protein levels; also, the production of ferritin was measured by WB.Results: the expression of HO-1 and the production of ferritin were significantly increased, but the expression of HO-2 was decreased.Furthermore, curcumin could significantly induce the protein and mRNA expression of PI3K, AKT and Nrf-2 (P<0.05), while the protective effects of curcumin were prevented by PI3K inhibitor LY294002 or Nrf-2 siRNA.Conclusion: Taken together, the data show that the cytoprotection of curcumin against oxidative stress in SH-SY5Y cells is by up-regulating HO-1 expression via PI3K/AKT/Nrf-2 intracellular signaling pathway and down-regulating HO-2 expression, all of which suggested that curcumin could be beneficial in the prevention and treatment of some CNS disease.