The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) induces complex neuronal signaling cascades that are critical for the cellular changes underlying synaptic plasticity. These pathways include activation of Ca2+ entry via N-methyl-D-aspartate receptors and sequential activation of nitric oxide synthase and NADPH oxidase, which via generation of reactive nitrogen/oxygen species stimulate Ca2+-induced Ca2+ release mediated by Ryanodine Receptor (RyR) channels. These sequential events underlie BDNF-induced spine remodeling and type-2 RyR up-regulation. In addition, BDNF induces the nuclear translocation of the transcription factor Nrf2, a master regulator of antioxidant protein expression that protects cells against the oxidative damage caused by injury and inflammation. To investigate the possible BDNF-induced signaling cascades that mediate Nrf2 nuclear translocation in primary hippocampal cultures, we tested here whether reactive oxygen species, RyR-mediated Ca2+ release, ERK or PI3K contribute to this response. We found that pre-incubation of cultures with inhibitory ryanodine to suppress RyR-mediated Ca2+ release, with the reducing agent N-acetylcysteine or with inhibitors of ERK or PI3K activity, prevented the nuclear translocation of Nrf2 induced by incubation for 6”¯h with BFNF. Based on these combined results, we propose that the key role played by BDNF as an inducer of neuronal antioxidant responses, characterized by BDNF-induced Nfr2 nuclear translocation, entails crosstalk between reactive oxygen species and RyR-mediated Ca2+ release, and the participation of ERK and PI3K activities.