Nrf2-signaling and BDNF: A new target for the antidepressant-like activity of chronic fluoxetine treatment in a mouse model of anxiety/depression

Several studies have shown that Nrf2, a major redox-sensitive transcription factor involved in the cellular defense against oxidative stress, increases susceptibility to depressive-like behavior. However, little is known about the influence of antidepressant drugs on Nrf2 signaling and expression of its target genes (GCLC,NQO1,HO-1)inthebrain.Wefoundthatchronictreatmentofamousemodelofanxiety/depression (CORT model) with a selective serotonin reuptake inhibitor (SSRI, fluoxetine, 18mg/kg/day) reversed CORT-induced anxiety/depression-like behavior in mice. Chronic fluoxetine treatment restored CORTinduceddecreasesinNrf2proteinlevelsanditstargetgenesinthecortexandhippocampus.Furthermore, we found that chronic fluoxetine also increased brain derived neurotrophic factor (BDNF) protein levels in cortex and hippocampus of CORT-treated Nrf2 knockout mice (KO,Nrf2 −/− ). Taken together, these data suggest that Nrf2 signaling contributes to fluoxetine-induced neuroprotectionviaan unexpected