Slusarczyk Joanna, Trojan Ewa, Glombik Katarzyna, Piotrowska Anna, Budziszewska Boguslawa, Kubera Marta, Popiolek-Barczyk Katarzyna, Lason Wladyslaw, Mika Joanna, Basta-Kaim Agnieszka
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Department of Pharmacology of Pain, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
J Neurochem. 2016 Mar;136(5):958-70. doi: 10.1111/jnc.13452.
Accumulating evidence suggests that activation of microglia plays a key role in the pathogenesis of depression. Activated microglia produce a wide range of factors whose prolonged or excessive release may lead to brain disorders. Thus, the inhibition of microglial cells may be beneficial in the treatment of depressive diseases. Tianeptine is an atypical antidepressant drug with proven clinical efficacy, but its mechanism of action remains still not fully understood. In the present study, using microglial cultures we investigated whether tianeptine modifies microglial activation after lipopolysaccharide (LPS) stimulation and which intracellular pathways are involved in the activity of this antidepressant. Our study shows that tianeptine attenuated the LPS-evoked inflammatory activation of microglia by decreasing the expression of proinflammatory cytokines such as IL-1β, IL-18, IL-6 and tumor necrosis factor α (TNF-α), the release of nitric oxide (NO) and reactive oxygen species (ROS) as well as the expression of inducible nitric oxide synthase. Analyses of signaling pathways demonstrate that tianeptine led to the suppression of LPS-induced TLR4 expression and ERK1/2 phosphorylation. Furthermore, our study reveals the inhibitory impact of tianeptine on caspase-3-induced PKCδ degradation and consequently on the activation of NF-κB factor in microglial cells. Taken together, present results show anti-inflammatory properties of tianeptine in microglial cultures stimulated by LPS. This study provides evidence that the inhibition of microglial activation may underlie the therapeutic activity of tianeptine. Our findings show the anti-inflammatory effect of tianeptine (TIA) in lipopolisaccharide (LPS)-stimulated microglial cells. The beneficial tianeptine action is mediated through the inhibition of Toll-like receptor 4 (TLR4) expression as well as the TLR4-related pathways: extracellular signal-regulated kinase 1/2 (ERK1/2), caspase-3-dependent protein kinase δ (PKCδ) cleavage and the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings may provide a new therapeutic strategy for treatment of disorders based on neuroinflammation, including depression.
越来越多的证据表明，小胶质细胞的激活在抑郁症发病机制中起关键作用。激活的小胶质细胞会产生多种因子，其长时间或过度释放可能导致脑部疾病。因此，抑制小胶质细胞可能对抑郁症治疗有益。噻奈普汀是一种临床疗效已得到证实的非典型抗抑郁药，但其作用机制仍未完全明确。在本研究中，我们利用小胶质细胞培养物，研究了噻奈普汀是否会改变脂多糖（LPS）刺激后的小胶质细胞激活情况，以及该抗抑郁药的活性涉及哪些细胞内信号通路。我们的研究表明，噻奈普汀通过降低促炎细胞因子如白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）、白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α）的表达、一氧化氮（NO）和活性氧（ROS）的释放以及诱导型一氧化氮合酶的表达，减轻了LPS诱导的小胶质细胞炎症激活。信号通路分析表明，噻奈普汀导致LPS诱导的Toll样受体4（TLR4）表达和细胞外信号调节激酶1/2（ERK1/2）磷酸化受到抑制。此外，我们的研究揭示了噻奈普汀对caspase-3诱导的蛋白激酶Cδ（PKCδ）降解的抑制作用，进而对小胶质细胞中核因子κB（NF-κB）因子激活的抑制作用。综上所述，目前的结果显示了噻奈普汀在LPS刺激的小胶质细胞培养物中的抗炎特性。本研究提供了证据表明，抑制小胶质细胞激活可能是噻奈普汀治疗活性的基础。我们的研究结果显示了噻奈普汀（TIA）在脂多糖（LPS）刺激的小胶质细胞中的抗炎作用。噻奈普汀的有益作用是通过抑制Toll样受体4（TLR4）表达以及与TLR4相关的信号通路来介导的：细胞外信号调节激酶1/2（ERK1/2）、caspase-3依赖性蛋白激酶δ（PKCδ）裂解以及活化B细胞核因子κB轻链增强子（NF-κB）的表达。这些发现可能为基于神经炎症的疾病（包括抑郁症）治疗提供新的治疗策略。
