Modulation of microglial activation by antidepressants

Abstract

Background: Recent studies have suggested that microglial activation plays a key role in the pathogenesis of depression. In fact, neuroinflammation is associated with a phenotypic change of microglia, consisting of morphological differences, increased release of cytokines and oxidative stress products, which may contribute to the development and maintenance of depression. Antidepressants, including selective serotonin re-uptake inhibitors and serotonin–norepinephrine reuptake inhibitors, have been shown to act on the immune and oxidative stress mechanisms commonly found to be disrupted in depression. Thus, the inhibition of microglial activation may be one of the mechanisms through which they exert an antidepressant action. Aim: This is the first review summarising in vitro and ex vivo studies investigating the effects of different classes of antidepressants on microglia activation, by examining cellular changes and/or via measuring the production of immune and/or oxidative stress signalling molecules, in microglia models of neuroinflammation with either lipopolysaccharide (LPS) or cytokines. A total of 23 studies were identified, 18 using LPS stimulation and 5 using cytokines stimulation. Results: Overall, the studies show that antidepressants, such as selective serotonin re-uptake inhibitors, serotonin–norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants prevented microglial activation, including reduced microglial reactivity and decreased immune and oxidative stress products, in both models. However, specific antidepressants, such as bupropion and agomelatine did not prevent interferon-gamma (IFN-γ)-induced microglial activation; and for other antidepressants, including phenelzine, venlafaxine and sertraline, the results of different studies were inconsistent. Conclusions: Overall, results summarised in this review support the hypothesis that the action of at least certain classes of antidepressants may involve regulation of microglial activation, especially when in presence of increased levels of inflammation.

Higher neutrophil–lymphocyte ratio is associated with depressive symptoms in Japanese general male population

“…Patients with a clinical diagnosis of depression are often treated with antidepressants. Some antidepressants can modulate microglial activation that plays a key role in neuroinflammation 30 . Thus, in the patients with a clinical diagnosis of depression, neuroinflammation may not necessarily reflected the CES-D scores.…”

A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury

“…Two isoforms of MAO encoded by MAOA and MAOB genes belong to the family of flavin-containing amine oxidoreductases, showing functional differences for their anatomic localization and major substrate ( Fisar, 2016 ; Shahid Nadeem et al, 2022 ). Previous studies have found that the inhibition of MAO activity can modulate LPS-induced microglial activation in vitro , suppressing the expression of pro-inflammatory factors ( Obuchowicz et al, 2006 ; Dhami et al, 2013 ; Park et al, 2020 ; Mariani et al, 2022 ). Rasagiline Mesylate (RM), a well-known irreversible MAO-B inhibitor, could suppress the expression of pro-inflammatory cytokines in LPS-treated BV2 cells ( Supplementary Figure S2 ).…”

Inhibition of Microglial Activation by Amitriptyline and Doxepin in Interferon-β Pre-Treated Astrocyte–Microglia Co-Culture Model of Inflammation

“…In vivo studies with animal models showed that antidepressants can reduce inflammation and oxidative stress, e.g., inhibitory effects on the expression of inflammatory mediators, including cytokines, as well as on microgliosis and astrogliosis, were detected [ 62 , 63 ]. Some antidepressants act through the same inflammatory and oxidative stress mechanisms commonly reported to be disrupted in depression, and this may represent one of the mechanisms through which they exert additional antidepressive effects.…”

“…Some antidepressants act through the same inflammatory and oxidative stress mechanisms commonly reported to be disrupted in depression, and this may represent one of the mechanisms through which they exert additional antidepressive effects. Because microglia are involved in the regulation of inflammation and oxidative stress, and antidepressants can prevent microglial activation in vitro and in animal models, the inhibition of microglial activation may play an important role, contributing to antidepressive effects [ 62 , 64 ]. Moreover, the inhibition of pro-inflammatory cytokines by antidepressants can contribute to antidepressive behavior, e.g., doxepin prevented stress-induced memory impairments and decreased TNF-α levels in the rat hippocampus, explaining one possible mechanism of pharmacological symptom control by antidepressants [ 54 ].…”