A method for biomarker measurements in peripheral blood mononuclear cells isolated from anxious and depressed mice: β-arrestin 1 protein levels in depression and treatment

Indira Mendez-David,René Hen,Saadia Kerdine-Römer,Denis J. David,Zeina El-Ali,Alain M. Gardier,Bruno Falissard,Emmanuelle Corruble

doi:10.3389/fphar.2013.00124

Abstract

A limited number of biomarkers in the central and peripheral systems which are known may be useful for diagnosing major depressive disorders and predicting the effectiveness of antidepressant (AD) treatments. Since 60% of depressed patients do not respond adequately to medication or are resistant to ADs, it is imperative to delineate more accurate biomarkers. Recent clinical studies suggest that β-arrestin 1 levels in human mononuclear leukocytes may be an efficient biomarker. If potential biomarkers such as β-arrestin 1 could be assessed from a source such as peripheral blood cells, then they could be easily monitored and used to predict therapeutic responses. However, no previous studies have measured β-arrestin 1 levels in peripheral blood mononuclear cells (PBMCs) in anxious/depressive rodents. This study aimed to develop a method to detect β-arrestin protein levels through immunoblot analyses of mouse PBMCs isolated from whole blood. In order to validate the approach, β-arrestin levels were then compared in na\\"{\\i}ve, anxious/depressed mice, and anxious/depressed mice treated with a selective serotonin reuptake inhibitor (fluoxetine, 18~mg/kg/day in the drinking water). The results demonstrated that mouse whole blood collected by submandibular bleeding permitted isolation of enough PBMCs to assess circulating proteins such as β-arrestin 1. β-Arrestin 1 levels were successfully measured in healthy human subject and na\\"{\\i}ve mouse PBMCs. Interestingly, PBMCs from anxious/depressed mice showed significantly reduced β-arrestin 1 levels. These decreased β-arrestin 1 expression levels were restored to normal levels with chronic fluoxetine treatment. The results suggest that isolation of PBMCs from mice by submandibular bleeding is a useful technique to screen putative biomarkers of the pathophysiology of mood disorders and the response to ADs. In addition, these results confirm that β-arrestin 1 is a potential biomarker for depression.

Highlights

Elucidation of the neurobiological bases of depression and anxiety are significant challenges for today’s society
The results demonstrated that mouse whole blood collected by submandibular bleeding permitted isolation of enough peripheral blood mononuclear cells (PBMCs) to assess circulating proteins such as β-arrestin 1. β-Arrestin 1 levels were successfully measured in healthy human subject and naïve mouse PBMCs
We examined whether changes in β-arrestin 1 levels in mouse PBMCs were observed in a model of anxiety/depression (David et al, 2009; Guilloux et al, 2011; Rainer et al, 2012b), and whether these levels could be corrected by chronic treatment with the Selective serotonin reuptake inhibitors (SSRIs) fluoxetine

Summary

Introduction

Elucidation of the neurobiological bases of depression and anxiety are significant challenges for today’s society. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressant (AD) drugs for major depressive disorders (MDD; Samuels et al, 2011). 60% of depression patients do not respond adequately or are resistant to these drugs (Samuels et al, 2011). There are clear benefits of having valid, reliable, selective, and feasible biomarkers for MDD. Candidate biomarkers that can accurately predict AD responses must be identified. Peripheral/serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and cytokines may serve as biomarkers of MDD and treatment response (for review, see Schmidt et al, 2011)

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