發(fā)布時(shí)間：2018-03-21 21:17

  本文選題：抑郁　切入點(diǎn)：替普瑞酮　出處：《昆明理工大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：抑郁癥是一種常見的心境障礙,主要由各種心理壓力、社會(huì)壓力、重大事故等多種因素造成,其主要的臨床特征為心情表現(xiàn)低落,情感缺乏和障礙,認(rèn)知出現(xiàn)障礙等。更為嚴(yán)重的是,有較大比例的抑郁癥病人會(huì)有自殺的動(dòng)機(jī)。因此,抑郁癥已經(jīng)成為社會(huì)性問題。抑郁癥的發(fā)病機(jī)理十分復(fù)雜,除了經(jīng)典的單胺假說、下丘腦-垂體-腎上腺軸假說等,氧化應(yīng)激,各種神經(jīng)營養(yǎng)因子與抑郁癥的發(fā)病和發(fā)展密切相關(guān)。另外,研究報(bào)道學(xué)習(xí)與記憶能力的損傷是抑郁癥的癥狀之一,突觸可塑性是學(xué)習(xí)與記憶的機(jī)制,突觸可塑性與抑郁癥的關(guān)系密切。突觸可塑性的變化受到谷氨酸的兩種受體的活性變化調(diào)控：N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)和α-氨基-3-羥基-5-甲基-4-異惡唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid,AMPA)受體。在抑郁模型中,NMDA受體的亞型NR2B受體的表達(dá)及AMPA受體的活性下降。 硫氧還蛋白(thioredoxin,Trx)具有氧化還原平衡調(diào)控的功能,還有促進(jìn)細(xì)胞生長的作用,已成為一類很好的用于治療各種氧化應(yīng)激疾病、衰老以及炎癥作用所誘發(fā)的疾病的藥物。所以,如何誘導(dǎo)Trx的表達(dá),并讓Trx靶向組織治療病變,已經(jīng)成為一個(gè)開發(fā)藥物的新方向。 熱休克蛋白70(heat shock protein70,Hsp70)是分子量為70kDa的熱休克蛋白,不論在真核還是原核細(xì)胞中,都可以檢測(cè)到其表達(dá)。當(dāng)細(xì)胞遭受應(yīng)激反應(yīng)時(shí),Hsp70最先做出反應(yīng),避免細(xì)胞的損傷。它在維持線粒體的正常生物功能的同時(shí)還能抑制細(xì)胞凋亡及壞死,并具有對(duì)抗炎癥反應(yīng)的作用。 在臨床上,替普瑞酮(geranylgeranylacetone,GGA)已經(jīng)廣泛地應(yīng)用,主要的應(yīng)用在胃腸道的潰瘍疾病治療中。近年的研究表明,在多個(gè)腦區(qū)的神經(jīng)元中、肝臟組織細(xì)胞中、視網(wǎng)膜的細(xì)胞中,以及腎衰竭、腦梗塞以及光損傷等造成的細(xì)胞損傷中,GGA可以誘導(dǎo)Trx表達(dá)量以及Hsp70的表達(dá)量升高,從而達(dá)到保護(hù)細(xì)胞損傷的作用。但是,GGA對(duì)于治療和預(yù)防抑郁癥還并見報(bào)道。 本課題通過構(gòu)建急性應(yīng)激誘導(dǎo)的小鼠抑郁模型,研究替普瑞酮對(duì)急性應(yīng)激誘導(dǎo)的抑郁的保護(hù)機(jī)制,研究其在動(dòng)物模型中對(duì)行為學(xué)變化及相關(guān)蛋白的表達(dá)調(diào)節(jié)機(jī)制。 主要研究結(jié)果如下： 1、GGA給予的小鼠對(duì)急性應(yīng)激具有抵抗作用,在懸尾與強(qiáng)迫游泳測(cè)試中,不動(dòng)時(shí)間顯著低于抑郁模型組；說明GGA具有抗小鼠急性應(yīng)激所致抑郁的作用。 2、GGA引起小鼠腦組織中Trx、Hsp70的表達(dá)上調(diào),起到抗氧化、神經(jīng)保護(hù)等作用；說明GGA通過調(diào)節(jié)Trx、Hsp70的表達(dá)抵抗細(xì)胞損傷。 3、GGA組的小鼠腦組織中,磷酸化的環(huán)磷腺苷效應(yīng)元件結(jié)合蛋白(cAMP-response element binding protein (CREB), p-CREB)表達(dá)量上調(diào)明顯,同時(shí)糖原合酶激酶3β(glycogen synthase kinase3β, GSK3β)的表達(dá)增加；說明GGA通過GSK3β途徑,以及CREB的磷酸化,促進(jìn)Trx的表達(dá)。 4、GGA對(duì)小鼠模型的突觸可塑性相關(guān)分子具有調(diào)節(jié)作用,起到抗抑郁藥的作用。在GGA組小鼠的海馬中,我們發(fā)現(xiàn)突觸可塑性調(diào)節(jié)相關(guān)的分子：CaMKⅡ,NR2B等蛋白都有明顯的變化。說明CaMKⅡ、NR2B與GGA的作用有關(guān)。 總結(jié)：GGA通過GSK3β途徑和p-CREB誘導(dǎo)Trx及Hsp70的表達(dá),對(duì)急性應(yīng)激誘導(dǎo)的小鼠抑郁具有保護(hù)性作用,同時(shí),GGA通過調(diào)節(jié)突觸可塑性的變化,起到抗抑郁藥的效果。該研究為預(yù)防及治療急性應(yīng)激引起的抑郁癥提供了基礎(chǔ)理論依據(jù)和新靶點(diǎn)。
[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.

【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R749.4

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 林安娣,馬昭芬;綜合治療15例急性應(yīng)激性精神障礙的體會(huì)[J];醫(yī)學(xué)文選;1995年03期

2 張鐘儒;兒童在急性應(yīng)激時(shí)β-內(nèi)啡肽水平[J];國外醫(yī)學(xué).內(nèi)分泌學(xué)分冊(cè);1991年02期

3 陳亞靜;史建勛;張冠雄;李亞;;急性應(yīng)激對(duì)小鼠空間學(xué)習(xí)記憶功能及腦內(nèi)GDNF表達(dá)的影響[J];科技信息;2012年09期

4 馬文濤 ,楊來啟 ,胡淑芳 ,吳興曲 ,劉光雄 ,王曉峰 ,張紅賓 ,李栓德 ,武勝昔;急性應(yīng)激對(duì)大鼠腦內(nèi)5-羥色胺2A受體mRNA表達(dá)的影響[J];中華精神科雜志;2002年04期

5 段寶玉;滕林;康九紅;聶奎;;急性應(yīng)激加速阿爾茨海默癥發(fā)生與發(fā)展[J];醫(yī)學(xué)研究雜志;2007年05期

6 吳少怡;許曉梅;;急性應(yīng)激后及時(shí)心理干預(yù)的有效性研究[J];精神醫(yī)學(xué)雜志;2008年04期

7 馬文濤,楊來啟,王曉峰,胡淑芳,吳興曲,劉光雄,張紅賓,武勝昔;急性應(yīng)激對(duì)大鼠腦內(nèi)5-羥色胺1A受體mRNA表達(dá)的影響[J];中國神經(jīng)精神疾病雜志;2002年06期

8 葉瑞印;曹曙光;;生長抑素在急性應(yīng)激致大鼠腸屏障功能損傷中的作用[J];浙江實(shí)用醫(yī)學(xué);2006年06期

9 程靈芝,李川云,劉曉紅,嚴(yán)進(jìn),黃麗婷;急性應(yīng)激干預(yù)的原則和方法[J];中國臨床康復(fù);2003年03期

10 王燕;陳艷;;40例老年期急性應(yīng)激性精神病臨床分析[J];臨床精神醫(yī)學(xué)雜志;2005年06期

相關(guān)會(huì)議論文 前3條

1 房圓;李華芳;錢伊萍;鄭賢杰;高嫻;李霞;;急性應(yīng)激抑郁模型大鼠不同腦區(qū)及外周血5-HT受體表達(dá)的變化[A];中華醫(yī)學(xué)會(huì)精神病學(xué)分會(huì)第九次全國學(xué)術(shù)會(huì)議論文集[C];2011年

2 陳愛勇;郭軍;陳公璞;陳海明;;嬰幼兒危重癥急性應(yīng)激性上消化道出血428例臨床分析[A];2000年全國危重病急救醫(yī)學(xué)學(xué)術(shù)會(huì)議論文集[C];2000年

3 張盛宇;禹順英;汪東祥;鄭賢杰;胡淑楠;李霞;;急性應(yīng)激抑郁模型大鼠中樞TPH2 mRNA表達(dá)及其與行為學(xué)變化的研究[A];中華醫(yī)學(xué)會(huì)精神病學(xué)分會(huì)第九次全國學(xué)術(shù)會(huì)議論文集[C];2011年

相關(guān)重要報(bào)紙文章 前1條

1 武漢大學(xué)人民醫(yī)院心理科 但加強(qiáng);休假歸來，他為何判若兩人？[N];大眾衛(wèi)生報(bào);2002年

相關(guān)博士學(xué)位論文 前3條

1 羅禹;急性應(yīng)激增強(qiáng)個(gè)體對(duì)威脅刺激的加工[D];西南大學(xué);2014年

2 張靜;去甲腎上腺素和IL-18在急性應(yīng)激影響小鼠接觸性皮炎中的作用機(jī)制研究[D];中南大學(xué);2009年

3 劉磊;糖皮質(zhì)激素通過快速非基因組機(jī)制抑制中性粒細(xì)胞性炎癥及提高急性應(yīng)激耐受力[D];第二軍醫(yī)大學(xué);2012年

相關(guān)碩士學(xué)位論文 前5條

1 段寶玉;急性應(yīng)激對(duì)實(shí)驗(yàn)鼠腦淀粉樣病變影響的研究[D];西南大學(xué);2007年

2 何恩其;水通道4敲除對(duì)小鼠急性應(yīng)激行為的影響及其機(jī)制[D];華中科技大學(xué);2011年

3 徐嘉珂;替普瑞酮抗急性應(yīng)激誘導(dǎo)的抑郁研究[D];昆明理工大學(xué);2014年

4 張智;急性應(yīng)激對(duì)大鼠腦中脫落酸變化的影響[D];中國科學(xué)技術(shù)大學(xué);2011年

5 崔久彩;急性應(yīng)激對(duì)海馬Akt/FKHRL1信號(hào)通路活性改變的影響[D];浙江大學(xué);2011年

，

本文編號(hào)：1645579