Elsevier

Neuroscience Letters

Volume 597, 15 June 2015, Pages 121-126
Neuroscience Letters

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

https://doi.org/10.1016/j.neulet.2015.04.036Get rights and content

Highlights

  • Nrf2 signaling is affected in a mouse model of anxiety/depression (the CORT model).

  • Chronic fluoxetine treatment restored these levels of expression.

  • Nrf2−/− mice (KO) display a decrease in BDNF protein levels.

  • Fluoxetine increased cortical and hippocampal BDNF in wild type and Nrf2−/− mice.

  • Fluoxetine-induced BDNF increase is Nrf2 independent.

Abstract

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, 18 mg/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.

Introduction

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are the most commonly prescribed antidepressant drugs for treatment of major depressive episodes. Unfortunately, SSRIs need 4 to 6 weeks to produce therapeutic responses and are only moderately effective since approximately 30% of depressed patients are resistant to antidepressant drugs [1], [2]. Thus, a major challenge in the pharmacological treatment of depression is to identify new biomarkers indicating whether or not antidepressant drugs will be effective. Identification of the precise cellular and molecular mechanisms underlying the efficiency and drawbacks of SSRIs may help to offer better treatments to depressed patients.

A possible relationship between inflammation and depression has received considerable attention in recent years. There is evidence that depression is accompanied by an increase in pro-inflammatory cytokines and a reduction in antioxidant defenses [3], [4]. Many antidepressant drugs decrease oxidative stress in chronically stressed animals [5], [6]. Chronic SSRI treatment may act by enhancing antioxidant defense mechanisms, but the precise cellular and molecular components of these mechanisms are still controversial [7].

The nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic leucine zipper transcription factor, plays a key role in the cellular defense against oxidative stress [8]. Chronic inflammation due to loss of Nrf2 leads to a depressive-like phenotype in Nrf2 knockout mice (Nrf2−/−). Furthermore, this depression-like phenotype in Nrf2−/− mice is associated with reduced tissue levels of monoamines in the prefrontal cortex, but not in the hippocampus [9].

Many Nrf2-dependent genes have been identified by microarray analysis [10]. Among them, glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H quinone oxidoreductase 1 (NQO1), and hemoxygenase (HO-1) are directly regulated by Nrf2 [11]. Thus, disruption or loss of Nrf2 signaling enhances susceptibility to cellular oxidative stress and to inflammatory injuries [12]. Although recent studies found little evidence that NQO1/GCLC polymorphisms associate with depression, these Nrf2 signaling components could be associated with the response to antidepressant drugs [13], [14].

The aim of the present study is to examine whether changes in protein levels of Nrf2 and antioxidant defensive enzymes (GCLC, NQO1, HO-1) in two brain regions involved in mood disorders, the cortex and hippocampus, can be reversed by chronic fluoxetine treatment in a mouse model of anxiety/depression based on the elevation of glucocorticoids (CORT model) [15], [16]. The CORT model, which was previously established and characterized by our lab and by others, mimics the effects of chronic stress and induces an anxiety/depression-like phenotype in several behavioral tests and molecular and cellular readouts.

In addition to an anxiety/depression-like phenotype, Nrf2 knockout mice (KO, Nrf2−/−) also display a reduction in brain-derived neurotrophic factor (BDNF) expression in the hippocampus [9]. A potential link between Nrf2 and neurotrophins (such as BDNF) is of interest considering the essential roles of neurotrophins in neuronal plasticity and network connectivity and in mood disorders and their treatments [17]. Thus, we also use Nrf2−/− mice to evaluate whether chronic fluoxetine-induced increases in cortical and hippocampal BDNF levels require the Nrf2-signalling pathway.

Section snippets

Animals

Adult male C57BL/6Ntac mice were purchased from Taconic Farms (Lille Skensved, Denmark). All mice were 7–8 weeks old, weighed 23–25 g at the beginning of the treatment, and were maintained on a 12 L:12 D schedule (lights on at 06:00). They were housed in groups of five. Food and water were provided ad libitum. All testing was conducted in compliance with the laboratory animal care guidelines and with protocols approved by the Institutional Animal Care and Use Committee (Council directive #

Effects of chronic fluoxetine treatment on cortical and hippocampal Nrf2 signaling in mice chronically treated with corticosterone

Prior to examining the Nrf2 pathway in the CORT model, we confirmed that chronic fluoxetine treatment reversed the corticosterone-induced anxio/depression-like phenotype in mice (Supplemental Fig. S1). In these animals, we next examined whether changes in cortical and hippocampal protein levels of Nrf2 and antioxidant defensive enzymes (GCLC, NQO1 and HO-1) are affected by chronic corticosterone and/or fluoxetine treatment.

In the cortex, chronic fluoxetine treatment (t = 2.76, *P < 0.05)

Discussion

Several phenomena have been investigated to better understand the pathophysiology of depression, including aberrations in neurotrophic factors, alterations in neurotransmitter and receptor signaling pathways, disturbances in the HPA axis, inflammation, immune dysfunctions, and imbalances between oxidative stress and antioxidant defenses.

There is now evidence that depression encompasses an inflammatory response associated with cell-mediated immune activation [22], [23]. Oxidative stresses

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    These authors contributed equally to this work.

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