替普瑞酮抗急性应激诱导的抑郁研究

发布时间：2018-03-21 21:17

本文选题：抑郁　切入点：替普瑞酮　出处：《昆明理工大学》2014年硕士论文　论文类型：学位论文

【摘要】：抑郁症是一种常见的心境障碍,主要由各种心理压力、社会压力、重大事故等多种因素造成,其主要的临床特征为心情表现低落,情感缺乏和障碍,认知出现障碍等。更为严重的是,有较大比例的抑郁症病人会有自杀的动机。因此,抑郁症已经成为社会性问题。抑郁症的发病机理十分复杂,除了经典的单胺假说、下丘脑-垂体-肾上腺轴假说等,氧化应激,各种神经营养因子与抑郁症的发病和发展密切相关。另外,研究报道学习与记忆能力的损伤是抑郁症的症状之一,突触可塑性是学习与记忆的机制,突触可塑性与抑郁症的关系密切。突触可塑性的变化受到谷氨酸的两种受体的活性变化调控：N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid,AMPA)受体。在抑郁模型中,NMDA受体的亚型NR2B受体的表达及AMPA受体的活性下降。硫氧还蛋白(thioredoxin,Trx)具有氧化还原平衡调控的功能,还有促进细胞生长的作用,已成为一类很好的用于治疗各种氧化应激疾病、衰老以及炎症作用所诱发的疾病的药物。所以,如何诱导Trx的表达,并让Trx靶向组织治疗病变,已经成为一个开发药物的新方向。热休克蛋白70(heat shock protein70,Hsp70)是分子量为70kDa的热休克蛋白,不论在真核还是原核细胞中,都可以检测到其表达。当细胞遭受应激反应时,Hsp70最先做出反应,避免细胞的损伤。它在维持线粒体的正常生物功能的同时还能抑制细胞凋亡及坏死,并具有对抗炎症反应的作用。在临床上,替普瑞酮(geranylgeranylacetone,GGA)已经广泛地应用,主要的应用在胃肠道的溃疡疾病治疗中。近年的研究表明,在多个脑区的神经元中、肝脏组织细胞中、视网膜的细胞中,以及肾衰竭、脑梗塞以及光损伤等造成的细胞损伤中,GGA可以诱导Trx表达量以及Hsp70的表达量升高,从而达到保护细胞损伤的作用。但是,GGA对于治疗和预防抑郁症还并见报道。本课题通过构建急性应激诱导的小鼠抑郁模型,研究替普瑞酮对急性应激诱导的抑郁的保护机制,研究其在动物模型中对行为学变化及相关蛋白的表达调节机制。主要研究结果如下： 1、GGA给予的小鼠对急性应激具有抵抗作用,在悬尾与强迫游泳测试中,不动时间显著低于抑郁模型组；说明GGA具有抗小鼠急性应激所致抑郁的作用。 2、GGA引起小鼠脑组织中Trx、Hsp70的表达上调,起到抗氧化、神经保护等作用；说明GGA通过调节Trx、Hsp70的表达抵抗细胞损伤。 3、GGA组的小鼠脑组织中,磷酸化的环磷腺苷效应元件结合蛋白(cAMP-response element binding protein (CREB), p-CREB)表达量上调明显,同时糖原合酶激酶3β(glycogen synthase kinase3β, GSK3β)的表达增加；说明GGA通过GSK3β途径,以及CREB的磷酸化,促进Trx的表达。 4、GGA对小鼠模型的突触可塑性相关分子具有调节作用,起到抗抑郁药的作用。在GGA组小鼠的海马中,我们发现突触可塑性调节相关的分子：CaMKⅡ,NR2B等蛋白都有明显的变化。说明CaMKⅡ、NR2B与GGA的作用有关。总结：GGA通过GSK3β途径和p-CREB诱导Trx及Hsp70的表达,对急性应激诱导的小鼠抑郁具有保护性作用,同时,GGA通过调节突触可塑性的变化,起到抗抑郁药的效果。该研究为预防及治疗急性应激引起的抑郁症提供了基础理论依据和新靶点。
[Abstract]:Depression is a common mood disorder, mainly by a variety of psychological pressure, social pressure, many kinds of factors causing serious accidents, the main clinical features of the mood is low, and lack of emotional disorder, cognitive obstacles. More seriously, there is a large proportion of the patients with depression have motivation. Therefore Dutch act depression, has become a social problem. The pathogenesis of depression is very complex, in addition to the classic monoamine hypothesis, the hypothalamic pituitary adrenal axis hypothesis, oxidative stress, various neurotrophic factors and depression are closely related to the onset and development. In addition, reports on the ability of learning and memory damage is one of the symptoms of depression. Synaptic plasticity is the mechanism of learning and memory, the relationship between synaptic plasticity and depression closely. The activity change of two kinds of receptor regulation of synaptic plasticity by glutamate: N - methyl -D- aspartate (N-methyl-D-aspartic acid, NMDA -3-) and alpha amino hydroxy -5- methyl -4- isoxazole propionate (-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid alpha, AMPA) receptor. In depression model, decreased NMDA receptor subtype NR2B receptor expression and AMPA receptor activity.
Thioredoxin (thioredoxin, Trx) with redox balance regulation function, and promote cell growth, has become a kind of good for the treatment of various oxidative stress disease, aging and disease drug induced inflammation. Therefore, how to induce the expression of Trx, and let Trx target tissue treatment disease, has become a new direction of development of a drug.
Heat shock protein 70 (heat shock, protein70, Hsp70) is a molecular weight of 70kDa, heat shock protein, either in eukaryotic or prokaryotic cells, its expression can be detected. When the cells exposed to stress reaction, Hsp70 first response, to avoid the injury of cells. It is in the maintenance of normal mitochondrial biology the function also can inhibit cell apoptosis and necrosis, and has anti inflammation.
In the clinic, teprenone (geranylgeranylacetone, GGA) has been widely used, mainly used in the treatment of ulcer disease of the gastrointestinal tract. Recent studies show that in some areas of the brain neurons, liver cells, retinal cells, and renal failure, cerebral infarction and photo damage etc. the cell damage, GGA can induce the expression of Trx and Hsp70 expression increased, thus protect cells from damage. However, the GGA for the treatment and prevention of depression are reported.
In this study, we constructed a mouse model of acute stress induced depression, studied the protective mechanism of teprone on acute stress induced depression, and studied its regulatory mechanism on behavioral changes and related protein expression in animal models.
The main results are as follows:
1, the mice given by GGA had resistance to acute stress. In the tail suspension test and forced swimming test, the immobility time was significantly lower than that in the depression model group, indicating that GGA has the effect of anti acute stress induced depression in mice.
2, GGA increased the expression of Trx and Hsp70 in mouse brain, and played an antioxidant and neuroprotective role, indicating that GGA resists cell damage by regulating the expression of Trx and Hsp70.
3, brain tissue of mice in group GGA, phosphorylation of cAMP responsive element binding protein (cAMP-response of element binding protein (CREB), p-CREB) was significantly up-regulated, while glycogen synthase kinase 3 beta (glycogen beta synthase kinase3, GSK3) increased the expression of GGA via GSK3 pathway; beta, and the phosphorylation of CREB, promote the expression of Trx.
4, related to synaptic plasticity in a mouse model of GGA molecule has a regulatory role to play the action of antidepressants. In the hippocampus of GGA mice, we found that the regulation of synaptic plasticity related molecules: CaMK II, NR2B protein has significant changes. CaMK II, NR2B and GGA..
Conclusion: expression of GGA induced by Trx and Hsp70 through the GSK3 beta pathway and p-CREB, acute stress induced depression in mice has a protective effect, at the same time, GGA through changes in the regulation of synaptic plasticity, plays an antidepressant effect. The study for the prevention and treatment of acute stress induced depression provides theoretical basis and a new target.

【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R749.4

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