Abstract
A growing body of evidence suggests that depression may be associated with impairment of the tryptophan catabolites (TRYCATs) pathway. The present study investigated the effects of the chronic administration of venlafaxine on the expression and methylation status of Katl, Tph1/2, Ido1, Kmo and Kynu in the brain and blood of rats exposed to the CMS model of depression. The rats were subjected to the CMS procedure for 2 or 7 weeks and administered venlafaxine (10 mg/kg/day, IP) for 5 weeks. mRNA and protein expression and the methylation status of gene promoters in PBMCs and six brain structures were evaluated and analysed using the TaqMan Gene Expression Assay and Western blotting, and methylation-sensitive high-resolution melting (MS-HRM), respectively. We found that the CMS procedure increased KatI expression in the midbrain and KatII expression in the midbrain and the amygdala, while venlafaxine administration decreased KatII expression in the hypothalamus and the cerebral cortex. The methylation status of the Tph1 and Kmo promoters in peripheral blood mononuclear cells (PBMCs) was significantly increased in the stressed group after antidepressant therapy. The protein levels of Tph1 and Ido1 were decreased following venlafaxine administration. Our results confirmed that CMS and venlafaxine modulate the expression levels and methylation status of genes involved in the TRYCATs pathway.
Highlights
According to a World Health Organization (WHO) report, 350 million people globally suffer from depression, and 800,000 people commit suicide every year (James et al 2018; Wang et al 2007)
The occurrence of TPH1, TPH2 and KATI polymorphisms may be associated with a lack of response to traditional therapy based on the application of selective serotonin reuptake inhibitors (SSRIs)
This study aimed to investigate whether (i) the chronic mild stress (CMS) procedure changes the expression of genes involved in the tryptophan catabolites (TRYCATs) pathway at the mRNA and protein levels and causes epigenetic changes, i.e. methylation level of these gene promoters in peripheral blood mononuclear cells (PBMCs) and in selected brain structures; and (ii) chronic administration of the serotoninnorepinephrine reuptake inhibitor venlafaxine affects the expression and methylation status of these genes
Summary
According to a World Health Organization (WHO) report, 350 million people globally suffer from depression, and 800,000 people commit suicide every year (James et al 2018; Wang et al 2007). A detailed description of the TRYCATs pathway is presented in previous studies have confirmed that depression is associated with reduced levels of tryptophan and neuroprotective kynurenic acid and elevated concentrations of neurotoxic metabolites, including 3-hydroxykynurenine, quinolinic acid and anthranilic acid, as well as with disorders of enzymes involved in tryptophan metabolism, including increased activity of indoleamine 2,3-dioxygenase 1 (IDO 1) and tryptophan 2,3-. Studying TRYCATs pathway in depression can provide new diagnostic biomarkers of this disease and may allow for the development of promising new personalized antidepressive drugs in the future (Smith 2013) This is of particular importance, as antidepressant treatment is not effective in approximately 30% of depressed patients (Joffe et al 1996), and recent studies have shown that a critical drop in the level of tryptophan is associated with the development of drug-resistant depression (Smith 2013). The presence of the T allele is associated with reduced TPH2 promoter activity (Smith 2013; Zhang et al 2005; Wigner et al 2018a, b)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
