Molecular Regulation of the Melatonin Biosynthesis Pathway in Unipolar and Bipolar Depression.

Monika Dmitrzak-Weglarz,Edyta Reszka,Ewa Jablonska,Karolina Bilska,Joanna Pawlak,Beata Narozna,Maria Skibinska,Aleksandra Szczepankiewicz,Paweł Kapelski,Ewa Banach

doi:10.3389/fphar.2021.666541

Abstract

Melatonin is a neurohormone that maintains the circadian rhythms of the body. By regulating the secretion of other hormones and neurotransmitters, it acts as a pleiotropic modulator that affects, for example, reproductive, immune, cardiovascular, sleep, and wake systems and mood. Thus, synthetic melatonin has become an essential component in the treatment of depressive disorders. Although we know the pathway of melatonin action in the brain, we lack comprehensive cross-sectional studies on the periphery of depressed patients. This study aimed to comprehensively analyze the differences between healthy control subjects (n = 84) and unipolar and bipolar depression patients (n = 94), including an analysis of the melatonin pathway at the level of the genes and serum biomarkers. An innovative approach is a pilot study based on gene expression profiling carried out on clinical and cell culture models using agomelatine and melatonin. We confirmed the melatonin biosynthesis pathway's molecular regulation dysfunctions, with a specific pattern for unipolar and bipolar depression, at the AANAT gene, its polymorphisms (rs8150 and rs3760138), and examined the serum biomarkers (serotonin, AANAT, ASMT, and melatonin). The biological pathway analysis uncovered pathways and genes that were uniquely altered after agomelatine treatment in a clinical model and melatonin treatment in a cell culture model. In both models, we confirmed the immunomodulatory effect of melatonin agents in depression.

Highlights

Depression in its various forms, especially unipolar (UD) and bipolar (BD) depression episodes, is a common disorder in modern societies, one which severely impairs the quality of life and social functioning
The study consisted of the following parts: genetic association analysis from peripheral blood, measurement of MEL biosynthesis pathway biomarkers (MBPBs) in serum, expression profiling analysis in PBMC after agomelatine treatment taken from depressed patients, and after MEL treatment of mice primary hippocampal neuron culture
The results suggest the existence of diverse, specific patterns of serum concentration of MBPBs for types of depression, which do not exclude the existence of tissue-specific patterns

Summary

Introduction

Depression in its various forms, especially unipolar (UD) and bipolar (BD) depression episodes, is a common disorder in modern societies, one which severely impairs the quality of life and social functioning. Based on the clinical picture alone, it is difficult to differentiate between depression episodes in terms of UD and BD. The search for laboratory markers that would facilitate the differentiation of types of depression has been carried out because incorrect diagnosis results in many years of inadequate, ineffective treatment associated with severe impairment of the patient’s functioning and health. Observations and clinical studies confirm the existence of differences between unipolar and bipolar depression on several levels: age of onset, relapse, family burden (Forty et al, 2008), or temperamental traits (Iasevoli et al, 2013; Fornaro et al, 2018). The cost and availability of the test limit its use in routine differential diagnoses

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