The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca2+ signals, ERK and PI3K

• Published in: Biochemical and biophysical research communications Vol. 505; no. 1; pp. 201 - 207
• Main Authors: Bruna, Bárbara, Lobos, Pedro, Herrera-Molina, Rodrigo, Hidalgo, Cecilia, Paula-Lima, Andrea, Adasme, Tatiana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.10.2018
• Subjects: 60 APPLIED LIFE SCIENCES; Antioxidant signaling; CALCIUM IONS; Calcium signaling; NERVE CELLS; Neuronal redox state; NITRIC OXIDE; OXIDASES; RATS; RECEPTORS; Synaptic plasticity; Transcription factor; Calcium signaling; Neuronal redox state; Transcription factor; Antioxidant signaling; Synaptic plasticity
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.09.080

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. •BDNF induced Nrf2 nuclear translocation in rat primary hippocampal neurons.•The antioxidant agent N-acetylcysteine suppressed Nrf2 nuclear translocation induced by BDNF.•Inhibition of RyR-mediated Ca2+ release suppressed Nrf2 nuclear translocation induced by BDNF.•Nrf2 nuclear translocation induced by BDNF required functional ERK1/2 and PI3K activities.