Journal
FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.01167
Keywords
inflammation; toll-like receptor; rheumatoid arthritis; antidepressant; mianserin; macrophage; 5-hydroxytryptamine; tumor necrosis factor
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Funding
- Imperial College London
- Medical Research Council [G1001715]
- Brighton and Sussex Medical School
- MRC [G1001715] Funding Source: UKRI
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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 radio-labelled 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.
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