Vortioxetine exerts anti‐inflammatory and immunomodulatory effects on human monocytes/macrophages

Abstract

BACKGROUND AND PURPOSEA crosstalk between the immune system and depression has been postulated, with monocytes/macrophages and cytokines having a key role in this interaction. In this study, we examined whether vortioxetine, a multimodal anti-depressive drug, was endowed with anti-inflammatory and antioxidative activity, leading to immunomodulatory effects on human monocytes and macrophages. EXPERIMENTAL APPROACHHuman monocytes were isolated from buffy coats and used as such or differentiated into M1 and M2 macrophages. Cells were treated with vortioxetine before or after differentiation, and their responsiveness was evaluated. This included oxy-radical and TNFα production, TNFα and PPARγ gene expression and NF-κB translocation. KEY RESULTSVortioxetine significantly reduced the PMA-induced oxidative burst in monocytes and in macrophages (M1 and M2), causing a concomitant shift of macrophages from the M1 to the M2 phenotype, demonstrated by a significant decrease in the expression of the surface marker CD86 and an increase in CD206. Moreover, treatment of monocytes with vortioxetine rendered macrophages derived from this population less sensitive to PMA, as it reduced the oxidative burst, NF-kB translocation, TNFα release and expression while inducing PPARγ gene expression. FACS analysis showed a significant decrease in the CD14 + /CD16 + /CD86 + M1 population. CONCLUSIONS AND IMPLICATIONSThese results demonstrate that in human monocytes/macrophages, vortioxetine has antioxidant activity and anti-inflammatory effects driving the polarization of macrophages towards their alternative phenotype. These findings suggest that vortioxetine, alongside its antidepressive effect, may have immunomodulatory properties. Abbreviations

Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors

“…To this purpose, we measured the effect of serotonin on PMA-induced oxidative burst in human monocytes. As previously shown, 1 mM serotonin reverses the oxidative burst to control values 33 . Known serotonin receptor antagonists ritanserin and ketanserin (10 mM) impaired serotonin action, while pure DGKa inhibitors such as Amb639752 had no effect (Figure 8).…”

“…Then, cells were stimulated with phorbol 12-myristate 13-acetate (PMA; Sigma-Aldrich, Milano, Italy) 1 mM for 30 min. PMA is a well-known stimulus that induces a strong and significant respiratory burst via PKC activation 33 . Superoxide anion production was then evaluated by the superoxide dismutase (SOD)-sensitive cytochrome C (CytC) reduction assay and expressed as nmoles CytC reduced/10 6 cells/ 30 min, using an extinction coefficient of 21.1 mM.…”

Cold Atmospheric Pressure Plasma Treatment Modulates Human Monocytes/Macrophages Responsiveness

“…corresponding control. We have previously shown that untreated monocytes do not change marker expression in a two-hour incubation and therefore the untreated control also depicts the baseline expression [36].…”

Insights into Macrophage Heterogeneity and Cytokine-Induced Neuroinflammation in Major Depressive Disorder

“…The SSRIs, paroxetine and sertraline, have a direct suppressive effect on microglial activation and pro-inflammatory cytokine secretion in mice [ 93 , 94 ]. Talmon et al demonstrated a significant role of alternatively-activated M2-macrophages and its anti-inflammatory effects in the treatment of depressive patients [ 95 ]. In patients taking the prescription drug vortioxetine, an antioxidant, drug treatment stimulated a phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst in monocytes, which polarized the cells from the M1 to the M2 phenotype [ 95 ].…”

“…Talmon et al demonstrated a significant role of alternatively-activated M2-macrophages and its anti-inflammatory effects in the treatment of depressive patients [ 95 ]. In patients taking the prescription drug vortioxetine, an antioxidant, drug treatment stimulated a phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst in monocytes, which polarized the cells from the M1 to the M2 phenotype [ 95 ]. Another group of drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are oftentimes used in combination with antidepressants.…”