【摘要】：目的與背景抑郁癥是臨床常見的精神疾病,估計(jì)到2020年將成為全球第二大疾病負(fù)擔(dān),僅次于缺血性心臟病。傳統(tǒng)抗抑郁藥物從開始治療到癥狀緩解需要數(shù)周時間,而且緩解率低。研究發(fā)現(xiàn)氯胺酮具有快速抗抑郁、神經(jīng)保護(hù)及抗炎等作用。單次給予亞麻醉劑量氯胺酮的抗抑郁作用特點(diǎn)是起效迅速,緩解率高,但維持時間較短。研究發(fā)現(xiàn)氯胺酮多次給藥可以維持其抗抑郁作用�；铙w和細(xì)胞學(xué)實(shí)驗(yàn)證實(shí)氯胺酮處理可抑制脂多糖誘導(dǎo)的小膠質(zhì)細(xì)胞激活以及脂多糖感染所致的肺部炎癥反應(yīng)。精神類疾病領(lǐng)域最近的研究進(jìn)展推測抑郁癥的發(fā)病機(jī)制涉及到炎癥過程以及腦與免疫系統(tǒng)之間的相互作用。然而,有關(guān)中樞小膠質(zhì)細(xì)胞及炎癥因子是否介導(dǎo)多次氯胺酮給藥的抗抑郁作用尚不清楚。因此,我們擬通過慢性不可預(yù)見輕度應(yīng)激(CUMS)抑郁癥大鼠模型,探討多次氯胺酮給藥在緩解大鼠抑郁樣行為的同時是否伴有小膠質(zhì)細(xì)胞狀態(tài)的改變以及炎癥細(xì)胞因子表達(dá)的改變,為今后新型抗抑郁藥物的研制提供思路和指導(dǎo)抑郁癥的治療。方法1.采用慢性不可預(yù)見輕度應(yīng)激(CUMS)方法建立抑郁樣大鼠模型。2.模型成功建立后通過腹腔多次注射氯胺酮,并再次進(jìn)行相關(guān)的相為學(xué)測試。3.通過酶聯(lián)免疫吸附試驗(yàn)(ELISA)檢測抑郁樣大鼠海馬炎癥細(xì)胞因子:TNF-α、IL-1β、IL-6的表達(dá)情況。4.采用蛋白質(zhì)印跡法(WB)檢測抑郁樣大鼠及多次氯胺酮給藥的抑郁樣大鼠海馬小膠質(zhì)細(xì)胞激活相關(guān)蛋白Iba1、CD11b表達(dá)情況。5.采用免疫組化(IHC)方法檢測抑郁樣大鼠及多次氯胺酮給藥的郁樣大鼠大鼠海馬CA3區(qū)、DG區(qū)CD11b陽性細(xì)胞數(shù)。結(jié)果1.采用慢性不可預(yù)見輕度應(yīng)激建立的抑郁樣大鼠模型,主要表現(xiàn)為大鼠糖水消耗百分比降低、強(qiáng)制游泳不動時間延長,而大鼠的活動度則不受影響。多次氯胺酮給藥后,抑郁樣大鼠糖水消耗百分比上升、強(qiáng)制游泳不動時間縮短,而大鼠的活動度不受影響。2.TNF-α、IL-1β、IL-6在抑郁樣大鼠海馬表達(dá)增加(p0.05),多次氯胺酮給藥后抑郁樣大鼠海馬TNF-α、IL-1β、IL-6表達(dá)降低(p0.05)。3.Iba1、CD11b蛋白在建模成功后的抑郁樣大鼠海馬中的表達(dá)增加(p0.05),而多次氯胺酮給藥后抑郁樣大鼠海馬Iba1、CD11b表達(dá)降低(p0.05)。4.CD11b陽性細(xì)胞數(shù)在建模成功后的抑郁樣大鼠海馬CA3區(qū)、DG區(qū)表達(dá)增加(p0.05),而多次氯胺酮給藥后抑郁樣大鼠海馬CA3區(qū)、DG區(qū)CD11b陽性細(xì)胞數(shù)表達(dá)降低(p0.05)。結(jié)論1.將實(shí)驗(yàn)大鼠暴露在慢性不可以預(yù)見輕度應(yīng)激環(huán)境中可導(dǎo)致抑郁樣行為,而多次氯胺酮給藥可將抑郁樣癥狀改善。2.抑郁樣大鼠海馬中炎癥細(xì)胞因子及小膠質(zhì)細(xì)胞激活相關(guān)蛋白表達(dá)增加,而多次氯胺酮給藥降低了炎癥細(xì)胞因子及與小膠質(zhì)細(xì)胞激活相關(guān)蛋白的表達(dá)。3.抑郁樣大鼠海馬中激活狀態(tài)的小膠質(zhì)細(xì)胞數(shù)量增加,而多次氯胺酮給藥后激活狀態(tài)的小膠質(zhì)細(xì)胞數(shù)量減少。
[Abstract]:Objective and background Depression is a common mental disease in clinic. It is estimated that depression will become the second largest disease burden in the world by 2020, second only to ischemic heart disease. Traditional antidepressants take weeks from the start of treatment to symptom relief, and the remission rate is low. Ketamine has been found to have rapid antidepressant, neuroprotective and anti-inflammatory effects. The antidepressant effect of single dose of ketamine was rapid, the remission rate was high, but the maintenance time was short. The study found that ketamine could maintain its anti-depressant effect after repeated administration. In vivo and cytological studies, ketamine treatment inhibited lipopolysaccharide-induced microglial activation and pulmonary inflammation induced by lipopolysaccharide infection. Recent advances in mental disorders suggest that the pathogenesis of depression involves inflammatory processes and the interaction between the brain and the immune system. However, it is unclear whether central microglia and inflammatory factors mediate the antidepressant effects of multiple ketamine administration. Therefore, we intend to explore whether multiple doses of ketamine can relieve depression in rats with microglia and inflammatory cytokines by using chronic unpredictable mild stress (CUMS) depression rat model. To provide ideas for the future development of new antidepressants and guide the treatment of depression. Method 1. The depressive rat model was established by chronic unpredictable mild stress (CUMS). 2. After the successful establishment of the model, ketamine was injected intraperitoneally several times, and related phase tests were performed again. 3. 3. The expression of TNF- 偽, IL-1 尾 and IL-6 in hippocampus of depressive rats was detected by enzyme linked immunosorbent assay (ELISA). 4. The expression of activation-associated protein (Iba1,CD11b) in hippocampal microglia of depressive rats and depressive rats treated with ketamine was detected by Western blot (WB). Immunohistochemical (IHC) method was used to detect the number of CD11b positive cells in the CA3 and DG regions of the hippocampus of depressive rats and those treated with ketamine. Result 1. The depressive rat model established by chronic unpredictable mild stress mainly showed that the percentage of sugar water consumption was decreased and the time of forced swimming immobility was prolonged but the activity of rats was not affected. After repeated ketamine administration, the percentage of sugar water consumption in depressive rats increased, and the immobility time of forced swimming was shortened. 2. The expression of TNF- 偽, IL-1 尾 and IL-6 in the hippocampus of depressive rats was increased (p0.05), and the expression of TNF- 偽, IL-1 尾, IL-6 in the hippocampus of depressive rats was decreased after multiple ketamine administration (p0.05). 3. The expression of Iba1 + CD11b protein in the hippocampus of depressive rats was increased (p0.05), and the expression of TNF- 偽, IL-1 尾, IL-6 in the hippocampus of depressive rats was increased (p0.05). The expression of Iba1,CD11b in the hippocampus of depressive rats after multiple ketamine administration was decreased (p0.05). The number of 4.CD11b positive cells was increased in the CA3 and DG regions of the depressive rats after modeling successfully (p0.05), while the expression of CD11b in the CA3 and DG regions of the hippocampus in the depressive rats after repeated ketamine administration was increased (p0.05). The number of positive cells decreased (p0.05). Conclusion 1. Exposure to chronic unanticipated mild stress could lead to depressive behavior, while multiple ketamine administration could improve depressive symptoms. 2. The expressions of inflammatory cytokines and microglial activation-associated proteins were increased in the hippocampus of depressive rats, while the expressions of inflammatory cytokines and microglial activation-associated proteins were decreased by multiple administration of ketamine. 3. The number of activated microglia in the hippocampus of depressive rats was increased, while the number of activated microglia was decreased after repeated ketamine administration.
【學(xué)位授予單位】：西南醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R749.4

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