硫氧还蛋白-1抑制甲基苯丙胺戒断的抑郁行为

发布时间：2019-02-17 08:22

【摘要】：甲基苯丙胺俗称“冰毒”,纯品外观为纯白结晶体,晶莹剔透,是中枢神经系统兴奋剂,长期使用会产生药物依赖,一旦甲基苯丙胺成瘾,戒断是十分不易的,在戒断期间出现的焦虑、抑郁、精神运动性迟滞等症状,严重影响患者的生理健康和心理健康等。甲基苯丙胺成瘾机制目前尚不明确,关于甲基苯丙胺成瘾机制的研究一直是生物医学的热点。甲基苯丙胺成瘾可引起氧化应激,导致机体氧化还原平衡状态的失调,从而引起机体损伤。硫氧还蛋白-1 (Thioredoxin-1, Trx-1)是机体内广泛存在的一种小分子量蛋白,也是一种重要的氧化还原调节蛋白,对维持机体的氧化还原平衡具有重要的作用,同时还具有促进细胞增殖、调节基因转录因子活性及抗凋亡等作用。Trx的分类可以分为三类,Trx-1、Trx-2以及在精子细胞中的特异的Trx-3,这些不同种类的Trx在细胞内作用各不相同。Trx-1是最常见的一类,也是分布最广泛的。Trx和NADPH以及Trx的还原酶(Thioredoxin reductase, TrxR)共同构成了Trx还原系统。抑郁症发病机制与单胺类递质、神经递质受体、神经营养因子、氧化应激、细胞因子、NO通路、神经变性等有关。抑郁症相关的脑区有海马和前额叶皮质(prefrontal cortex, PFC)等脑区。本研究通过构建METH所致条件位置偏好(conditioned place preference, CPP)模型,确定METH可以导致成瘾行为,通过一周的自然戒断后,使用经典的悬尾实验方法检测抑郁行为,比较两组间“不动状态”的时间差异,发现METH戒断的小鼠会产生抑郁行为,而Trx-1高表达小鼠能够抵抗METH戒断引起的抑郁行为。其次,检测海马区和PFC区Trx-1、cAMP反应元件结合蛋白(cAMP response element binding protein, CREB)、周期素依赖蛋白激酶(cyclin-dependent kinase 5, CDK5)、单胺氧化酶(monoamine oxidase，，MAO)、5-羟色胺转运体(serotonin transporter,5-HTT)、N-甲基-D-天门冬氨酸(N-methyl-D-aspartate, NMDA)受体的亚基NR2B、谷氨酸受体1(glutamate receptor 1, GluR1)以及钙调素依赖性蛋白激酶(Ca2+/calmodulin-dependent protein kinase, CaMKⅡ)等蛋白水平的表达发现METH引起的小鼠Trx-1、CREB、CDK5蛋白的变化,而Trx-1高表达小鼠能够抵抗METH引起的这些分子变化,同时METH戒断引起MAO和ST蛋白水平的升高,引起NR2B、GluR1、p-CaMKⅡ蛋白水平的降低,而Trx-1高表达小鼠对这种变化均有恢复作用。总结：Trx-1高表达可以抑制METH戒断所致的抑郁行为,其作用机理是通过恢复DA,5-HT,谷氨酸途径,因此,Trx-1可以作为METH成瘾戒断行为治疗的一个新的靶点。
[Abstract]:Methamphetamine, commonly known as "methamphetamine," has a pure white crystal appearance, is crystal clear, is a central nervous system stimulant, long-term use will produce drug dependence, once methamphetamine addiction, withdrawal is very difficult, The symptoms of anxiety, depression and mental retardation during withdrawal seriously affect the patients' physical and mental health. The mechanism of methamphetamine addiction is still unclear, and the research on the mechanism of methamphetamine addiction has been a hot topic in biomedicine. Methamphetamine addiction can lead to oxidative stress, resulting in imbalance of redox balance, which can lead to body damage. Thioredoxin 1 (Thioredoxin-1, Trx-1) is a small molecular weight protein and an important redox regulatory protein, which plays an important role in maintaining redox balance. Trx can be classified into three categories: Trx-1,Trx-2 and specific Trx-3, in sperm cells. Trx-1 is the most common and widely distributed. Trx, NADPH and Trx reductase (Thioredoxin reductase, TrxR) together form the Trx reduction system. The pathogenesis of depression is related to monoamine transmitter, neurotransmitter receptor, neurotrophic factor, oxidative stress, cytokine, NO pathway, neurodegeneration and so on. Depression related brain regions include hippocampus and prefrontal cortex (prefrontal cortex, PFC) and other brain regions. In this study, (conditioned place preference, CPP) model of conditional position preference induced by METH was constructed to determine that METH can lead to addictive behavior. After a week of natural withdrawal, depression behavior was detected by classical tail suspension test. By comparing the time difference of "immobility" between the two groups, it was found that METH abstinent mice had depressive behavior, while Trx-1 high expression mice could resist depressive behavior caused by METH withdrawal. Secondly, cyclin-dependent kinase 5 (CDK5), monoamine oxidase,MAO and (serotonin transporter, Trx-1,cAMP response element binding protein (cAMP response element binding protein, CREB), (CDK5) in hippocampus and PFC region were detected. 5-HTT, N-methyl-D-aspartate (NMDA) receptor subunit NR2B, (glutamate receptor 1 (GluR1) and Ca2 / calmodulin-dependent protein kinase, The expression of CaMK 鈪

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