Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin, China.
Department of Neurology, Affliated Hospital of Yanbian University, Yanji 133000, Jilin, China.
Int Immunopharmacol. 2019 Feb;67:119-128. doi: 10.1016/j.intimp.2018.12.011. Epub 2018 Dec 10.
Evidence indicates that inflammation plays a crucial role in depression. Therefore, new antidepressants might be identified by screening drugs for their anti-inflammatory actions. Sertraline 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 [TNF-α], interleukin-1β [IL-1β] and inducible nitric oxide synthase [iNOS]) 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.
证据表明，炎症在抑郁症中起着至关重要的作用。因此，通过筛选药物的抗炎作用，可能会发现新的抗抑郁药。盐酸舍曲林（SERT）是一种广泛使用的抗抑郁药，在临床研究中具有抗炎作用，但涉及的机制尚不清楚。在这项研究中，我们使用细胞和分子生物学来确定 SERT 在体内和体外的可能抗炎机制。体内研究的实验数据表明，与对照组相比，暴露于慢性不可预测轻度应激（CUMS）的小鼠在外周和中枢组织中具有明显更高水平的主要炎症细胞因子（肿瘤坏死因子-α[TNF-α]，白细胞介素-1β[IL-1β]和诱导型一氧化氮合酶[iNOS]）。用 SERT 治疗 CUMS 小鼠可显著降低这些炎症细胞因子的水平，并抑制核因子-κB（NF-κB）和 B 细胞κ轻肽基因增强子核因子抑制剂，α（IκB-α）的磷酸化。此外，SERT 降低了 CUMS 小鼠血清中转氨酶的水平。我们的体外研究表明，SERT 以剂量依赖性方式抑制 TNF-α诱导的 NF-κB 激活。SERT 还通过抑制 IκB-α磷酸化来抑制 TNF-α诱导的 NF-κB 核易位。此外，SERT 抑制 BV2 小胶质细胞中 TNF-α诱导的炎症细胞因子。SERT 直接与 TNF-α和 TNF-α受体 1（TNFR1）结合，以有效阻断 TNF-α/TNFR1 触发的信号。这些结果表明，SERT 可能通过抑制 NF-κB 信号通路中微胶质细胞的激活来治疗抑郁症。这项研究为研究和开发具有减轻炎症和炎症介质表达作用的抗抑郁药提供了依据。
