發(fā)布時(shí)間：2018-11-16 07:03

【摘要】：抑郁癥作為一類(lèi)最常見(jiàn)的精神疾病,其主要以顯著而持久的心境低落為臨床特征，其發(fā)病機(jī)制復(fù)雜，尚未完全闡明。近年來(lái)相關(guān)研究證據(jù)表明，機(jī)體神經(jīng)炎癥反應(yīng)及介導(dǎo)的神經(jīng)退行性病變?cè)谝钟舭Y的發(fā)病機(jī)制中扮演著重要的角色。據(jù)此細(xì)胞因子假說(shuō)，作為中樞神經(jīng)系統(tǒng)內(nèi)常駐免疫細(xì)胞即小膠質(zhì)細(xì)胞的過(guò)度活化及其釋放的炎性細(xì)胞因子在抑郁癥發(fā)病機(jī)制中的作用與抗抑郁藥的藥理機(jī)制也提出了新的觀點(diǎn)�，F(xiàn)有研究已顯示，細(xì)胞介導(dǎo)的免疫應(yīng)激反應(yīng)可激活中樞神經(jīng)系統(tǒng)內(nèi)神經(jīng)免疫細(xì)胞-小膠質(zhì)細(xì)胞的活化，其活化產(chǎn)生的大量促炎細(xì)胞因子誘導(dǎo)吲哚胺2，3-雙加氧酶（IDO）,一方面IDO可消耗血漿中色氨酸（TRP）的含量，使合成5-HT的原料減少，另一方面其可通過(guò)色氨酸-犬尿氨酸（TRYCATs）通路分解TRP產(chǎn)生的毒性物質(zhì)能夠損害神經(jīng)系統(tǒng)造成神經(jīng)性退行性病變，以上這些均有可能致使抑郁癥的發(fā)生。 因而，本次實(shí)驗(yàn)利用脂多糖（LPS）誘導(dǎo)小膠質(zhì)細(xì)胞模擬神經(jīng)炎癥反應(yīng)環(huán)境，建立免疫異常細(xì)胞模型，觀察阿司匹林（ASA）與氟西汀(FLX)是否對(duì)小膠質(zhì)細(xì)胞活化存在一定的抑制作用，并在此基礎(chǔ)上我們進(jìn)一步探討了二者在模擬的神經(jīng)炎癥反應(yīng)環(huán)境中相關(guān)藥理機(jī)制，為抑郁藥物的合理使用提供一定的實(shí)驗(yàn)理論依據(jù)。 實(shí)驗(yàn)研究顯示，F(xiàn)LX可濃度依賴(lài)性地抑制脂多糖誘導(dǎo)的BV-2小膠質(zhì)細(xì)胞上清液中IL-1β含量及IDO酶蛋白表達(dá)水平同時(shí)有效抑制了TRP含量的減少，在與小劑量聯(lián)合使用ASA后可增強(qiáng)這一效果。進(jìn)一步研究發(fā)現(xiàn)，F(xiàn)LX可抑制LPS誘導(dǎo)的小膠質(zhì)細(xì)胞p38MAPK通路以及NF-κBp65的活化以及IκBa蛋白的降解，，而在與ASA聯(lián)合使用后，其還對(duì)ERK1/2通路具有一定的抑制能力。綜合以上結(jié)果，我們FLX聯(lián)合ASA可抑制活化小膠質(zhì)細(xì)胞內(nèi)炎癥介質(zhì)IL-1β的釋放，減少細(xì)胞內(nèi)TRP的消耗。而且這種作用可能是通過(guò)抑制NF-κB，p38MAPK以及ERK1/2三條信號(hào)通路實(shí)現(xiàn)的。由此進(jìn)一步闡明了相關(guān)藥物的藥理機(jī)制并為抗抑郁藥的合理使用提供了新的依據(jù)。
[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.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R749.4

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

1 王銀;;抑郁癥藥物治療的研究進(jìn)展[J];安徽醫(yī)藥;2010年02期

2 馬智超;;自殺未遂與血清膽固醇濃度及相關(guān)基因多態(tài)性關(guān)系的研究進(jìn)展[J];疾病預(yù)防控制通報(bào);2011年04期

3 林立元;;抑郁癥易患性性別差異原因及機(jī)制的研究進(jìn)展[J];福建中醫(yī)藥;2010年03期

4 陳瑞玲;趙志剛;;抗抑郁癥類(lèi)藥物的臨床應(yīng)用研究進(jìn)展[J];中國(guó)臨床藥理學(xué)雜志;2007年01期

5 張璐璐;鄭洪波;;細(xì)胞因子與抑郁癥[J];國(guó)際精神病學(xué)雜志;2007年02期

6 鄭蕾;王藝明;;帕羅西汀治療抑郁癥后血清神經(jīng)營(yíng)養(yǎng)因子3的變化[J];貴陽(yáng)醫(yī)學(xué)院學(xué)報(bào);2013年04期

7 方雷;安建平;趙輝;毛軍峰;李運(yùn);代偉;;~(13)N-Ammonia PET心肌灌注顯像與CT冠狀動(dòng)脈造影在冠心病診斷中的價(jià)值比較[J];安徽醫(yī)學(xué);2013年09期

8 馬卓;陳月;馮婉玉;;度洛西汀與艾司西酞普蘭治療抑郁癥療效與安全性的系統(tǒng)評(píng)價(jià)[J];中國(guó)臨床藥理學(xué)雜志;2013年12期

9 熊永強(qiáng);;針刺通調(diào)任督法治療廣泛性焦慮癥的臨床觀察[J];光明中醫(yī);2013年12期

10 唐嬋;王芳;張敏;蔣慧;唐飄;;慢性阻塞性肺疾病患者穩(wěn)定期的健康管理[J];當(dāng)代護(hù)士(中旬刊);2013年12期

相關(guān)會(huì)議論文 前4條

1 ;Suicide study and suicide prevention in mainland China[A];全國(guó)第九屆危機(jī)干預(yù)及自殺預(yù)防學(xué)術(shù)年會(huì)論文匯編（二）[C];2011年

2 郭園麗;;青年及中老年腦卒中患者可逆性危險(xiǎn)因子的差異性分析[A];河南省外科創(chuàng)傷及災(zāi)難救治護(hù)理專(zhuān)科知識(shí)學(xué)術(shù)會(huì)議（神經(jīng)科學(xué)組）論文集[C];2011年

3 周驥;牟U

本文編號(hào)：2334800