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) in the brain. We found that chronic treatment of a mouse model of anxiety/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 CORT-induced decreases in Nrf2 protein levels and its target genes in the cortex and hippocampus. 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 neuroprotection via an unexpected mechanism involving 5-HT transporter SERT blockade, and not through enhancement of BDNF expression.
Univ Paris Sud, INSERM UMR S 1178, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France.
Indira
I
Mendez-David
Univ Paris Sud, INSERM UMR S 1178, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France.
Laurent
L
Tritschler
Univ Paris Sud, INSERM UMR 996, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France.
Zeina El
ZE
Ali
Univ Paris Sud, INSERM UMR 996, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France.
Marie-Hélène
MH
Damiens
Univ Paris Sud, INSERM UMR 996, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France.
Marc
M
Pallardy
Univ Paris Sud, INSERM UMR S 1178, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France.
Denis J
DJ
David
Univ Paris Sud, INSERM UMR 996, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France.
Saadia
S
Kerdine-Römer
Univ Paris Sud, INSERM UMR S 1178, Fac Pharmacie, Univ Paris-Saclay, Châtenay-Malabry, F-92290, France. Electronic address: alain.gardier@u-psud.fr.
Alain M
AM
Gardier
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D005473:Fluoxetine; D003345:Corticosterone
Animal model of anxiety/depression; Antidepressant; BDNF; Nrf2 pathway