本文選題：去鐵胺 + 神經(jīng)炎癥反應(yīng)　； 參考：《中國(guó)人民解放軍醫(yī)學(xué)院》2015年碩士論文

【摘要】：第一部分 脂多糖(LPS)腦室注射誘發(fā)認(rèn)知功能障礙動(dòng)物模型的建立目的探討脂多糖單次腦室注射對(duì)C57小鼠認(rèn)知功能的影響,以期建立中樞炎性相關(guān)的認(rèn)知功能障礙的小鼠模型。方法將40只C57小鼠隨機(jī)分為5組,分別為溶劑對(duì)照組與LPS 10ng、100ng、2000ng,5000ng劑量組,進(jìn)行Morris水迷宮(MWM)實(shí)驗(yàn)。于第1-5日進(jìn)行水迷宮空間獲得性訓(xùn)練,第6日腦室單次分別給予LPS 0、10、100、2000、5000ng,第7-9日進(jìn)行水迷宮空間探索實(shí)驗(yàn)與工作記憶檢測(cè)。結(jié)果與溶劑對(duì)照組相比,脂多糖給藥組均引起小鼠在Morris水迷宮實(shí)驗(yàn)中認(rèn)知功能下降,其中2000ng LPS給藥組分別引起水迷宮空間探索實(shí)驗(yàn)中小鼠穿臺(tái)次數(shù)、平臺(tái)周邊路程、目標(biāo)象限停留時(shí)間百分比及目標(biāo)象限停留路程百分比均顯著減少,工作記憶檢測(cè)中登臺(tái)潛伏期明顯延長(zhǎng)(P0.05)。小結(jié)單次LPS(2μg)(?)室注射可引起C57小鼠認(rèn)知功能障礙,提示LPS腦室注射導(dǎo)致炎性損傷可以作為認(rèn)知功能障礙的候選模型。第二部分去鐵胺(DFO)對(duì)LPS誘發(fā)小鼠認(rèn)知功能障礙的改善及機(jī)制目的探討DFO對(duì)LPS誘發(fā)小鼠認(rèn)知損傷的改善作用及機(jī)制。方法將48只C57小鼠隨機(jī)分為6組,分別為溶劑對(duì)照組、LPS模型組與DFO 0.1μg、0.5μg、2.5μg、5μg治療組,進(jìn)行Morris水迷宮(MWM)實(shí)驗(yàn)以探索DFO對(duì)LPS誘發(fā)認(rèn)知障礙的改善的最佳劑量。另將100只C57小鼠隨機(jī)分為4四組：溶劑對(duì)照組、DFO組、LPS組和LPS+DFO組。0.5μg DFO于2μg LPS腦室注射前3日給藥,對(duì)照組給予等量人工腦脊液,給藥方式均為側(cè)腦室注射。每日行為學(xué)實(shí)驗(yàn)或給藥前進(jìn)行小鼠體質(zhì)量測(cè)量。LPS給藥6h、24h、48h、72h后將小鼠行心臟灌流并取腦,通過檢測(cè)海馬組織中小膠質(zhì)細(xì)胞狀態(tài)、IL-1p和TNF-α水平、細(xì)胞凋亡蛋白caspase-3與糖原合酶激酶3β(glycogen synthase kinase 3β, GSK3β)表達(dá)、超氧化物歧化酶(superoxide dismutase, SOD)和丙二醛(malondialdehyde,MDA)活性及海馬組織鐵代謝狀態(tài)的改變等指標(biāo)以評(píng)估LPS引起的小鼠海馬損傷及DFO的神經(jīng)保護(hù)作用及可能機(jī)制。結(jié)果DFO預(yù)給藥明顯改善了LPS引起的小鼠在Morris水迷宮實(shí)驗(yàn)中認(rèn)知樣行為的下降,而并未對(duì)自發(fā)活動(dòng)造成明顯改變。DFO減輕了LPS誘發(fā)的海馬組織小膠質(zhì)細(xì)胞激活與炎癥因子IL-1β和TNF-α的上升,同時(shí)預(yù)防性減弱了caspase-3蛋白的(P0.05)表達(dá)增多、GSK3β激活及MDA與SOD水平的改變。DFO明顯逆轉(zhuǎn)LPS引起的海馬組織鐵沉積及鐵代謝相關(guān)蛋白的表達(dá)水平變化(P0.05)。小結(jié)DFO通過阻止神經(jīng)細(xì)胞內(nèi)鐵沉積,減弱海馬神經(jīng)組織炎癥反應(yīng)、氧化應(yīng)激與凋亡等病理進(jìn)程,最終對(duì)LPS誘發(fā)的小鼠認(rèn)知功能障礙起到改善作用。結(jié)論：LPS腦室注射觸發(fā)小鼠中樞神經(jīng)炎癥級(jí)聯(lián)反應(yīng)與腦鐵沉積,從而導(dǎo)致短暫性認(rèn)知功能障礙；DFO可對(duì)脂多糖誘發(fā)的小鼠神經(jīng)炎癥反應(yīng)與記憶損傷起到保護(hù)作用,這一作用可能與維持腦鐵含量較低水平從而起到的神經(jīng)保護(hù)性作用及應(yīng)激反應(yīng)與凋亡水平的改善有關(guān)。
[Abstract]:Part one: establishment of animal model of cognitive dysfunction induced by intraventricular injection of lipopolysaccharide (LPS) objective to investigate the effect of single intraventricular injection of lipopolysaccharide on cognitive function of C57 mice in order to establish a model of central inflammatory related cognitive dysfunction. Methods Forty C57 mice were randomly divided into 5 groups: solvent control group and LPS 10ng / 100ng / 100ng / 100ng / kg group. The Morris water labyrinth test was carried out. The water labyrinth spatial acquisition training was conducted on the 1st to 5th day, the sixth ventricle was given LPS 010100 / 2000000ng, and the water labyrinth spatial exploration experiment and working memory test were carried out on the 7th and 9th days. Results compared with the solvent control group, the lipopolysaccharide group caused the decrease of cognitive function in the Morris water maze test, and the 2000ng LPS group caused the mice to penetrate the platform and the distance around the platform in the water maze space exploration experiment. The percentage of target quadrant residence time and the percentage of target quadrant residence distance were significantly reduced, and the latency of stage entry was significantly prolonged in working memory testing (WMA). Single LPS(2 渭 g) Ventricular injection could induce cognitive dysfunction in C57 mice, suggesting that LPS injection could be used as a candidate model for cognitive dysfunction. The second part: the improvement and mechanism of LPS induced cognitive dysfunction in mice by deferoxamine DFOObjective to investigate the effect and mechanism of DFO on LPS induced cognitive impairment in mice. Methods Forty-eight C57 mice were randomly divided into 6 groups: the solvent control group and the DFO 0.1 渭 g, 0.5 渭 g or 2.5 渭 g, 5 渭 g treatment group. The Morris water maze test was performed to explore the best dose of DFO to improve the cognitive impairment induced by LPS. In addition, 100 C57 mice were randomly divided into four groups: the solvent control group and the LPS DFO group received intraventricular injection of 0.5 渭 g DFO 3 days before intracerebroventricular injection, and the control group was given the same amount of artificial cerebrospinal fluid (ACSF), all of which were administered by intracerebroventricular injection. The body mass of mice was measured by daily behavioral experiment or before administration of LPS. The mice were perfused with heart for 72 h after administration of LPS for 24 h or 48 h. The levels of IL-1p and TNF- 偽 in hippocampal tissue were measured by detecting the status of mesomatous glial cells in hippocampus. The expression of apoptotic protein caspase-3 and glycogen synthase kinase 3 尾 (GSK3 尾) was observed. The activity of superoxide dismutase (SOD) and malondialdehyde (malondialdehyde) MDAs and the changes of iron metabolism in hippocampal tissue were used to evaluate the neuroprotective effect of LPS and DFO in mice. Results DFO preadministration significantly improved the reduction of cognitive-like behavior in mice induced by LPS in Morris water maze test. There was no obvious change in spontaneous activity. DFO alleviated the activation of microglia and the increase of inflammatory cytokines IL-1 尾 and TNF- 偽 in hippocampus induced by LPS. At the same time, the expression of caspase-3 protein increased and GSK3 尾 activation and the changes of MDA and SOD levels. DFO significantly reversed the changes of iron deposition and iron metabolism-related protein expression in hippocampus induced by LPS. Conclusion DFO can improve the cognitive function of mice induced by LPS by preventing iron deposition in nerve cells, weakening inflammatory reaction, oxidative stress and apoptosis in hippocampal nerve tissue. Conclusion the neuroinflammatory cascade reaction and iron deposition in the central nervous system were triggered by intraventricular injection of 10% LPS in mice, which resulted in transient cognitive impairment. DFO can protect the neuroinflammatory response and memory impairment induced by lipopolysaccharide in mice. This effect may be related to the neuroprotective effect of maintaining a low level of iron in the brain and the improvement of the level of apoptosis and the stress response.
【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R614

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