Cadmium (Cd) , a widely toxic metal, induces apoptosis in neuronal cells.In our previous study, we found that Cd induced the generation of reactive oxygen species (ROS) and mitochondrial pathway played an important role in Cd-induced apoptosis in both rat primary cerebral cortical neurons and PC12 cells.Studies have demonstrated that Cd induces apoptosis of neuronal cells (PC12 and SH-SY5Y) in part by activation of protein kinase B and mammalian target of rapamycin (Akt/mTOR) pathways.However, whether Cd activates mitochondrial and AKT/mTOR pathways via induction of ROS in neuronal cells remain elusive.In this study, primary rat cerebral cortical neurons and PC12 cells were exposed to Cd, which significantly decreased the B-cell lymphoma 2/Bcl-2 associated X protein ((Bcl-2/Bax) ratio and increased the percentage of apoptotic cells, release of cytochrome c,cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP), and nuclear translocation of apoptosis-inducing factor (AIF).In addition, exposure to Cd decreased protein expression of PTEN (phosphatase and tensin homologue on chromosome 10) and induced phosphorylation of Akt, mTOR and its downstream effector molecules, p70 S6 kinase 1 (S6K1), eukaryotic initiation factor 4E-binding protein 1 (4E-BP1).Rapamycin, an inhibitor of mTOR,partially attenuated Cd-induced phosphorylation of Akt, mTOR, S6K1, and 4E-BP1, as well as apoptosis of the neuronal cells.Pretreatment with N-acetyl-L-cysteine (NAC) , a ROS scavenger, effectively reversed decrease of Bcl-2/Bax ratio,release of cytochrome c, cleavages of caspase-3 and PARP, and nuclear translocation of AIF,phosphorylation of Akt, mTOR, S6K1, and 4E-BP1, as well as apoptosis of the neuronal cells.All together, these results demonstrated that the ROS-mediated AKT/mTOR pathway and mitochondrial apoptotic pathway (involving caspase-dependent and caspase-independent pathways) plays an important role in Cd-induced neuronal apoptosis.