阿司匹林联合氟西汀对脂多糖诱导小胶质细胞活性的影响及其机制研究

发布时间：2018-11-16 07:03

【摘要】：抑郁症作为一类最常见的精神疾病,其主要以显著而持久的心境低落为临床特征，其发病机制复杂，尚未完全阐明。近年来相关研究证据表明，机体神经炎症反应及介导的神经退行性病变在抑郁症的发病机制中扮演着重要的角色。据此细胞因子假说，作为中枢神经系统内常驻免疫细胞即小胶质细胞的过度活化及其释放的炎性细胞因子在抑郁症发病机制中的作用与抗抑郁药的药理机制也提出了新的观点。现有研究已显示，细胞介导的免疫应激反应可激活中枢神经系统内神经免疫细胞-小胶质细胞的活化，其活化产生的大量促炎细胞因子诱导吲哚胺2，3-双加氧酶（IDO）,一方面IDO可消耗血浆中色氨酸（TRP）的含量，使合成5-HT的原料减少，另一方面其可通过色氨酸-犬尿氨酸（TRYCATs）通路分解TRP产生的毒性物质能够损害神经系统造成神经性退行性病变，以上这些均有可能致使抑郁症的发生。因而，本次实验利用脂多糖（LPS）诱导小胶质细胞模拟神经炎症反应环境，建立免疫异常细胞模型，观察阿司匹林（ASA）与氟西汀(FLX)是否对小胶质细胞活化存在一定的抑制作用，并在此基础上我们进一步探讨了二者在模拟的神经炎症反应环境中相关药理机制，为抑郁药物的合理使用提供一定的实验理论依据。实验研究显示，FLX可浓度依赖性地抑制脂多糖诱导的BV-2小胶质细胞上清液中IL-1β含量及IDO酶蛋白表达水平同时有效抑制了TRP含量的减少，在与小剂量联合使用ASA后可增强这一效果。进一步研究发现，FLX可抑制LPS诱导的小胶质细胞p38MAPK通路以及NF-κBp65的活化以及IκBa蛋白的降解，，而在与ASA联合使用后，其还对ERK1/2通路具有一定的抑制能力。综合以上结果，我们FLX联合ASA可抑制活化小胶质细胞内炎症介质IL-1β的释放，减少细胞内TRP的消耗。而且这种作用可能是通过抑制NF-κB，p38MAPK以及ERK1/2三条信号通路实现的。由此进一步阐明了相关药物的药理机制并为抗抑郁药的合理使用提供了新的依据。
[Abstract]:Depression, as the most common mental disease, is characterized by significant and persistent depression. The pathogenesis of depression is complex and has not been fully elucidated. Recent studies have shown that neuroinflammatory responses and neurodegenerative disorders play an important role in the pathogenesis of depression. Based on the cytokine hypothesis, the role of inflammatory cytokines in the pathogenesis of depression and the pharmacological mechanism of antidepressants are also proposed as the excessive activation and release of inflammatory cytokines in the resident immune cells of the central nervous system (CNS), that is, microglia. Current studies have shown that cell-mediated immune stress can activate neuroimmune cell-microglial activation in the central nervous system, which produces a large number of pro-inflammatory cytokines to induce indoleamine 2o 3-dioxygenase (IDO),. On the one hand, IDO can consume the content of tryptophan (TRP) in plasma and reduce the raw material for 5-HT synthesis. On the other hand, it can break down the toxic substances produced by TRP through the tryptophan-canine (TRYCATs) pathway, which can damage the nervous system and cause neurodegenerative lesions, which may lead to depression. Therefore, in this experiment, lipopolysaccharide (LPS) was used to induce microglia to mimic the neuroinflammatory reaction environment and to establish an immune abnormal cell model. To observe whether aspirin (ASA) and fluoxetine (FLX) can inhibit the activation of microglia, we further explore the pharmacological mechanism of aspirin (ASA) and fluoxetine (FLX) in the simulated neuroinflammatory response environment. To provide a certain experimental theoretical basis for the rational use of depressive drugs. The experimental results showed that FLX could inhibit IL-1 尾 content and IDO protein expression in lipopolysaccharide induced BV-2 microglia supernatant in a concentration-dependent manner and inhibit the decrease of TRP content. This effect can be enhanced when combined with small doses of ASA. Furthermore, it was found that FLX could inhibit the activation of p38MAPK pathway, NF- 魏 Bp65 and the degradation of I 魏 Ba protein in microglia induced by LPS. After combined with ASA, FLX could inhibit ERK1/2 pathway to a certain extent. In addition, our FLX combined with ASA can inhibit the release of IL-1 尾, an inflammatory mediator in activated microglia, and reduce the consumption of TRP in cells. Moreover, this effect may be achieved by inhibiting three signaling pathways of NF- 魏 B p38 MAPK and ERK1/2. The pharmacological mechanism of related drugs is further clarified and a new basis for rational use of antidepressants is provided.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R749.4

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