The Effect of Chronic Mild Stress and Escitalopram on the Expression and Methylation Levels of Genes Involved in the Oxidative and Nitrosative Stresses as Well as Tryptophan Catabolites Pathway in the Blood and Brain Structures

Paulina Wigner,Piotr Gruca,Janusz Szemraj,Tomasz Śliwiński,Paweł Jóźwiak,Piotr Czarny,Mariusz Papp,Michał Bijak,Ewelina Synowiec,Katarzyna Białek

doi:10.3390/ijms22010010

Abstract

Previous studies suggest that depression may be associated with reactive oxygen species overproduction and disorders of the tryptophan catabolites pathway. Moreover, one-third of patients do not respond to conventional pharmacotherapy. Therefore, the study investigates the molecular effect of escitalopram on the expression of Cat, Gpx1/4, Nos1/2, Tph1/2, Ido1, Kmo, and Kynu and promoter methylation in the hippocampus, amygdala, cerebral cortex, and blood of rats exposed to CMS (chronic mild stress). The animals were exposed to CMS for two or seven weeks followed by escitalopram treatment for five weeks. The mRNA and protein expression of the genes were analysed using the TaqMan Gene Expression Assay and Western blotting, while the methylation was determined using methylation-sensitive high-resolution melting. The CMS caused an increase of Gpx1 and Nos1 mRNA expression in the hippocampus, which was normalised by escitalopram administration. Moreover, Tph1 and Tph2 mRNA expression in the cerebral cortex was increased in stressed rats after escitalopram therapy. The methylation status of the Cat promoter was decreased in the hippocampus and cerebral cortex of the rats after escitalopram therapy. The Gpx4 protein levels were decreased following escitalopram compared to the stressed/saline group. It appears that CMS and escitalopram influence the expression and methylation of the studied genes.

Highlights

Depression is a serious mental illness which is believed to affect 350 million people worldwide, according to the WHO
In the case of the Cat, Nos2, and genes involved in tryptophan catabolites (TRYCATs) pathway, no significant differences were observed between any studied groups
In the case of genes involved in TRYCATs pathway, Tph1 expression in the cerebral cortex was elevated following escitalopram treatment compared to the stressed group (H = 12.433, df = 4, p = 0.014, Tukey test p < 0.05) and the stressed group receiving saline treatment (H = 12.433, df = 4, p = 0.014, Tukey test p < 0.05)

Summary

Introduction

Depression is a serious mental illness which is believed to affect 350 million people worldwide, according to the WHO. It has been recognized as the third leading cause of disability in 2015 [1]. The condition affects both sexes, women are approximately twice as likely to develop symptoms [2]. Depression can lead to suicide attempts, and approximately one million people commit suicide every year [3,4]. Depression is associated with high economic costs, constituting about 60% of the total cost of treating all mental conditions [5]. More than a third of patients suffer from treatment-resistant depression [6]

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