慢性应激性抑郁发生中转化生长因子-β1与硒蛋白P的作用及其关系

发布时间：2018-06-26 00:42

本文选题：抑郁 + 应激　；参考：《陕西师范大学》2013年硕士论文

【摘要】：抑郁症是一种高发病率、高死亡率及高复发率的情感障碍性精神疾病。慢性应激是引起抑郁症发生的一个关键因素。在现代社会,生活节奏不断加快,人们面临的各种生活、社会压力不断增加,致使抑郁症的发病也呈逐年上升的趋势,这给人们生活以及国家经济发展带来极大的负担。据世界卫生组织预测,到2030年,抑郁症可能成为全球负担最大的疾病。关于抑郁症的发病机制,主要从神经递质与受体失调、神经可塑性等方面研究较多。而近年来神经免疫在抑郁症发生中的作用越来越引起人们的关注。转化生长因子-β1(Transforming growth factor-beta1, TGF-β1)不仅在控制炎症、免疫反应以及组织损伤中发挥重要作用,且通过多种途径对神经发挥保护作用。研究发现,抑郁症中TGF-β1表达异常。硒蛋白P (Selenoprotein P, SelP)对硒转运及维持体内硒平衡,维持正常脑功能非常重要。硒蛋白P与一些神经退行性疾病有关。硒蛋白P基因敲除导致神经损伤,突触可塑性改变,由此引起空间学习记忆以及运动协调能力的改变。一氧化氮(nitricoxide, NO)过多导致神经损伤从而引发抑郁,iNOS拮抗剂具有抗抑郁效应。有研究表明,TGF-β1抑制硒蛋白P的表达,且TGF-β1通过下调iNOS表达负性调控NO的产生。这些研究结果提示,抑郁发生与TGF-β1、硒蛋白P和NO是有关系的。海马结构和功能的改变与抑郁症的发生密切相关,然而,在应激性抑郁发生中,海马内TGF-β1、硒蛋白P和NO的变化、作用及其相互关系并不清楚,也没有系统的研究和报道。因此,本实验通过建立慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)抑郁模型,海马内微量注射TGF-β1以及TGF-βⅠ型受体激酶抑制剂LY-364947,测量体重变化率,运用糖水消耗实验、旷场实验以及悬尾实验检测大鼠行为变化,并采用免疫组织化学、酶联免疫吸附(ELISA)和western blot方法检测大鼠海马内TGF-β1和硒蛋白P的变化,硝酸还原试剂盒检测NO含量的变化,试图探讨慢性不可预见性温和应激中TGF-β1的作用及其与硒蛋白P、NO的关系。实验结果如下： 1、与正常对照组相比,CUMS大鼠表现出明显的抑郁样行为；应激导致海马内TGF-β1含量显著升高,硒蛋白P表达显著下降。 2、正常大鼠海马内注射TGF-β1并不导致抑郁样行为,相反,CUMS同时海马内注射TGF-β1明显改善应激诱导的抑郁样行为；正常和CUMS大鼠海马注射TGF-β1,均能明显抑制硒蛋白P的表达。 3、应激的同时注射LY-364947阻断TGF-β1信号通路同样具有抗抑郁效应,此时硒蛋白P表达较CUMS组明显升高。 4、各组内NO的含量没有显著性变化。以上结果表明海马TGF-β1与硒蛋白P参与了慢性应激反应,硒蛋白P对海马可能具有保护作用。TGF-β1可能通过TGF-βⅠ型受体抑制硒蛋白P的表达参与抑郁症的发生,而TGF-β1的抗抑郁作用可能是经过TGF-βⅠ型受体以外的其它途径实现的。降低NO的含量可能不是TGF-β1及硒蛋白P发挥作用的关键。
[Abstract]:Depression is a kind of emotional disorder with high morbidity, high mortality and high recurrence rate. Chronic stress is a key factor causing depression. In modern society, the rhythm of life is accelerating, people are facing all kinds of life, and social pressure is increasing, which causes the trend of depression to increase year by year. People's lives and the economic development of the country pose a great burden. According to WHO, by 2030, depression may become the biggest burden in the world.
The pathogenesis of depression is mainly from neurotransmitters and receptor disorders, neuroplasticity and other aspects. In recent years, the role of neuroimmunology in the development of depression has attracted more and more attention. Transforming growth factor - beta 1 (Transforming growth factor-beta1, TGF- beta 1) is not only in control of inflammation, immune response and group. It is important to play an important role in the damage to the nerve. It is found that the expression of TGF- beta 1 is abnormal in depression. Selenoprotein P (Selenoprotein P, SelP) is very important for selenium transport and maintenance of selenium balance in the body and maintenance of normal brain function. Selenoprotein P is related to some neurodegenerative diseases. Selenoprotein P knockout It causes nerve damage, synaptic plasticity changes, resulting in changes in spatial learning and memory and movement coordination. Nitric oxide (nitricoxide, NO) leads to nerve damage and causes depression, and iNOS antagonists have antidepressant effects. Studies have shown that TGF- beta 1 inhibits the expression of selenoprotein P, and TGF- beta 1 reduces the negative expression of iNOS by downregulating the expression of iNOS Regulation of the production of NO. These findings suggest that depression is related to TGF- beta 1, selenoprotein P and NO. Changes in the structure and function of the hippocampus are closely related to the occurrence of depression. However, in the occurrence of stress depression, the changes in the TGF- beta 1, selenoprotein P and NO in the hippocampus are not clear, and there is no systematic study. And reports.
Therefore, by establishing a chronic unpredictable mild stress (chronic unpredictable mild stress, CUMS) depression model, microinjection of TGF- beta 1 in the hippocampus and LY-364947 of the TGF- beta kinase inhibitor kinase inhibitor, the rate of body weight change was measured, and the behavior changes of rats were detected by using sugar water consumption experiment, open field experiment and tail suspension test. The changes of TGF- beta 1 and selenoprotein P in the hippocampus of rats were detected by immunohistochemistry, enzyme linked immunosorbent assay (ELISA) and Western blot, and the changes of NO content were detected by the nitrate reduction kit. The effects of TGF- beta 1 on chronic unpredictable mild stress and the relationship with the selenium protein P and NO were investigated. The experimental results were as follows:
1, compared with the normal control group, CUMS rats showed significant depressive behavior. Stress resulted in a significant increase in the TGF- beta 1 content in the hippocampus and a significant decrease in selenoprotein P expression.
2, injection of TGF- beta 1 in the hippocampus of normal rats did not lead to depressive like behavior. On the contrary, CUMS injection of TGF- beta 1 in the hippocampus significantly improved the depressive behavior induced by stress, and TGF- beta 1 in the hippocampus of normal and CUMS rats could significantly inhibit the expression of selenoprotein P.
3, the simultaneous injection of LY-364947 and TGF- beta 1 signaling pathway also had antidepressant effect. The expression of selenoprotein P was significantly higher than that in CUMS group.
4, there was no significant change in the content of NO in each group.
The above results show that hippocampal TGF- beta 1 and selenoprotein P participate in chronic stress response. Selenoprotein P may have protective effect on hippocampus.TGF- beta 1 may participate in the occurrence of depression by inhibiting the expression of selenoprotein P by TGF- beta type I receptor, and the antidepressant effect of TGF- beta 1 may be achieved through other pathways other than TGF- beta type I receptor. Low NO content may not be the key to TGF- beta 1 and selenoprotein P.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.4

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