Structural Modification of the Antidepressant Mianserin Suggests That Its Anti-inflammatory Activity May Be Independent of 5-Hydroxytryptamine Receptors.

Sandra Sacre,Caroline M R Low,Giselle Chamberlain,Cathy Tralau-Stewart,Albert Jaxa-Chamiec

doi:10.3389/fimmu.2019.01167

Abstract

Antidepressants are increasingly recognized to have anti-inflammatory properties in addition to their ability to treat major depressive disorders. To explore if engagement of 5-hydroxytryptamine (5-HT) receptors was required for the anti-inflammatory effect of the tetracyclic antidepressant mianserin, a series of structural derivatives were generated with the aim of reducing 5-HT receptor binding. Primary human peripheral blood mononuclear cells were used to screen for anti-inflammatory activity. The lead compound demonstrated a significant loss in 5-HT receptor binding, as assessed by non-selective 5-HT binding of radiolabelled serotonin in rat cerebral cortex. However, it retained the ability to inhibit endosomal toll-like receptor 8 signaling in primary human macrophages and spontaneous cytokine production from human rheumatoid synovial tissue equivalent to that previously observed for mianserin. These data demonstrate that the anti-inflammatory mechanism of mianserin may be independent of 5-HT receptor activity. This research offers new insights into the mechanism and structural requirements for the anti-inflammatory action of mianserin.

Highlights

Antidepressants have been used for decades in the treatment of major depressive disorders (MDD)
As we had previously demonstrated an anti-inflammatory effect of mianserin on endosomal toll-like receptor (TLR) signaling, a human Peripheral blood mononuclear cells (PBMCs) assay was used to screen for activity of the structural derivatives against TLR8 activation
R-848 was used as a ligand for TLR8; this is a dual ligand for TLR7, it is thought to act solely through TLR8 in human monocytes and macrophages as these cells do not produce tumor necrosis factor (TNF) in response to TLR7 ligands

Summary

Introduction

Antidepressants have been used for decades in the treatment of major depressive disorders (MDD). These drugs consist of several classes, each with varying mechanisms of action that modulate monoaminergic signaling [1]. It has been increasingly acknowledged that many antidepressants have an additional anti-inflammatory activity, that may contribute toward the clinical benefit of these drugs when treating MDD [2]. MDD can occur as a comorbidity of many chronic inflammatory diseases such as rheumatoid arthritis (RA), where cytokines are systemically elevated [4]. Data from a meta-analysis study, suggests that the use of anti-cytokine therapies such as anti-TNF, improves depressive symptoms in patients being treated for chronic inflammatory diseases including rheumatoid arthritis [5]

Methods

Results

Conclusion