Daniele Simona, Da Pozzo Eleonora, Zappelli Elisa, Martini Claudia
Department of Pharmacy, University of Pisa, Italy.
Department of Pharmacy, University of Pisa, Italy.
Cell Signal. 2015 Aug;27(8):1609-29. doi: 10.1016/j.cellsig.2015.04.006. Epub 2015 Apr 21.
Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α), which efficiently mimic the stress-related changes in neurotrophic and pro-inflammatory genes. Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-γ) in neuronal-like cells. In contrast, neuronal cell treatment with LPS and TNF-α decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-κB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (i.e., interleukin-6 and IFN-γ) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-α. In addition, the production of inflammatory mediators was inhibited, and the release of interleukin-10 was restored to control levels. Furthermore, the intracellular signalling mechanism regulating TDZ-elicited effects was specifically investigated. TDZ induced extracellular signal-regulated kinase (ERK) phosphorylation and inhibited constitutive p38 activation. Moreover, TDZ counteracted the activation of p38 and c-Jun NH2-terminal kinase (JNK) elicited by LPS-TNF-α, suggesting that the neuro-protective role of TDZ could be mediated by p38 and JNK. Overall, our results demonstrated that the protective effects of TDZ under inflammation in neuronal-like cells function by decreasing pro-inflammatory signalling and by enhancing anti-inflammatory signalling.
越来越多的证据表明，炎症/免疫系统的改变促成了重度抑郁症的发病机制，且炎症过程可能影响抗抑郁治疗反应。抑郁症患者在外周和大脑中的炎症标志物水平均升高，抑郁症与伴有炎症改变的疾病之间存在高共病率。曲唑酮（TDZ）是一种三唑并吡啶衍生物，属于5-羟色胺受体拮抗剂和再摄取抑制剂类药物。尽管经典抗抑郁药的营养和保护特性已得到广泛研究，但TDZ的作用仍有待充分阐明。在本研究中，我们在生理和炎症条件下研究了TDZ对人神经元样细胞的药理活性。使用脂多糖（LPS）和肿瘤坏死因子-α（TNF-α）建立了体外炎症模型，该模型有效模拟了神经营养和促炎基因中与应激相关的变化。我们的结果表明，TDZ显著增加了神经元样细胞中脑源性神经因子（BDNF）和cAMP反应元件结合蛋白（CREB）的mRNA表达，并降低了促炎细胞因子干扰素-γ（IFN-γ）的细胞释放。相反，用LPS和TNF-α处理神经元细胞会降低CREB和BDNF的表达，并增加核因子κB（NF-κB）的表达，NF-κB是一种在炎症反应起始中起作用的主要转录因子。此外，这两种药物会诱导促炎细胞因子（即白细胞介素-6和IFN-γ）的释放，并降低抗炎细胞因子白细胞介素-10的产生。TDZ预处理完全逆转了细胞活力的下降，并抵消了LPS-TNF-α介导的BDNF和CREB表达的降低。此外，炎症介质的产生受到抑制，白细胞介素-10的释放恢复到对照水平。此外，我们还专门研究了调节TDZ诱导效应的细胞内信号传导机制。TDZ诱导细胞外信号调节激酶（ERK）磷酸化并抑制组成型p38激活。此外，TDZ抵消了LPS-TNF-α引起的p38和c-Jun氨基末端激酶（JNK）的激活，这表明TDZ的神经保护作用可能由p38和JNK介导。总体而言，我们的结果表明，TDZ在炎症条件下对神经元样细胞的保护作用是通过减少促炎信号传导和增强抗炎信号传导来实现的。
