Sertraline ameliorates inflammation in CUMS mice and inhibits TNF-α-induced inflammation in microglia cells

Lu, Y.; Xu, X.; Jiang, T.; Jin, L.; Zhao, X. D.; Cheng, J. H.; Jin, X. J.; Ma, J.; Piao, H. N.; Piao, L. X., Sertraline ameliorates inflammation in CUMS mice and inhibits TNF-α-induced inflammation in microglia cells. Int Immunopharmacol 2019, 67, 119-128.

Interaction Type: Protein-small molecule

Abstract: Evidence indicates that inflammation plays a crucial role in depression. Therefore, new antidepressants might be identified by screening drugs for their anti-inflammatory actionsSertraline hydrochloride (SERT), a widely used antidepressant, has anti-inflammatory effects in clinical studies, but the mechanism involved is unclear. In this study, we used cell and molecular biology to determine the possible anti-inflammatory mechanism of SERT in vivo and in vitro. Experimental data from the in vivo study showed that mice exposed to chronic unpredictable mild stress (CUMS) had significantly higher levels of major inflammatory cytokines (tumor necrosis factor-α , interleukin-1β and inducible nitric oxide synthase ) in peripheral and central tissues compared with the control group. Treatment of CUMS mice with SERT significantly reduced the levels of these inflammatory cytokines and inhibited the phosphorylation of nuclear factor-κB (NF-κB) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). Moreover, SERT reduced serum levels of transaminase in CUMS mice. Our in vitro study revealed that SERT suppressed TNF-α-induced NF-κB activation in a dose-dependent manner. SERT also inhibited the TNF-α-induced nuclear translocation of NF-κB by inhibiting IκB-α phosphorylation. Furthermore, SERT inhibited TNF-α-induced inflammatory cytokines in BV2 microglia cells. SERT directly bound to TNF-α and TNF-α receptor 1 (TNFR1) to potently block TNF-α/TNFR1-triggered signaling. These results indicate that SERT might treat depression by inhibiting the activation of microglia via the NF-κB signaling pathway. This study provides a basis for the research and development of antidepressants that act to reduce inflammation and the expression of inflammatory mediators.

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