多次氯胺酮给药对抑郁样大鼠海马小胶质细胞和炎症细胞因子表达的影响
发布时间：2018-10-18 11:26
【摘要】：目的与背景抑郁症是临床常见的精神疾病,估计到2020年将成为全球第二大疾病负担,仅次于缺血性心脏病。传统抗抑郁药物从开始治疗到症状缓解需要数周时间,而且缓解率低。研究发现氯胺酮具有快速抗抑郁、神经保护及抗炎等作用。单次给予亚麻醉剂量氯胺酮的抗抑郁作用特点是起效迅速,缓解率高,但维持时间较短。研究发现氯胺酮多次给药可以维持其抗抑郁作用。活体和细胞学实验证实氯胺酮处理可抑制脂多糖诱导的小胶质细胞激活以及脂多糖感染所致的肺部炎症反应。精神类疾病领域最近的研究进展推测抑郁症的发病机制涉及到炎症过程以及脑与免疫系统之间的相互作用。然而,有关中枢小胶质细胞及炎症因子是否介导多次氯胺酮给药的抗抑郁作用尚不清楚。因此,我们拟通过慢性不可预见轻度应激(CUMS)抑郁症大鼠模型,探讨多次氯胺酮给药在缓解大鼠抑郁样行为的同时是否伴有小胶质细胞状态的改变以及炎症细胞因子表达的改变,为今后新型抗抑郁药物的研制提供思路和指导抑郁症的治疗。方法1.采用慢性不可预见轻度应激(CUMS)方法建立抑郁样大鼠模型。2.模型成功建立后通过腹腔多次注射氯胺酮,并再次进行相关的相为学测试。3.通过酶联免疫吸附试验(ELISA)检测抑郁样大鼠海马炎症细胞因子:TNF-α、IL-1β、IL-6的表达情况。4.采用蛋白质印迹法(WB)检测抑郁样大鼠及多次氯胺酮给药的抑郁样大鼠海马小胶质细胞激活相关蛋白Iba1、CD11b表达情况。5.采用免疫组化(IHC)方法检测抑郁样大鼠及多次氯胺酮给药的郁样大鼠大鼠海马CA3区、DG区CD11b阳性细胞数。结果1.采用慢性不可预见轻度应激建立的抑郁样大鼠模型,主要表现为大鼠糖水消耗百分比降低、强制游泳不动时间延长,而大鼠的活动度则不受影响。多次氯胺酮给药后,抑郁样大鼠糖水消耗百分比上升、强制游泳不动时间缩短,而大鼠的活动度不受影响。2.TNF-α、IL-1β、IL-6在抑郁样大鼠海马表达增加(p0.05),多次氯胺酮给药后抑郁样大鼠海马TNF-α、IL-1β、IL-6表达降低(p0.05)。3.Iba1、CD11b蛋白在建模成功后的抑郁样大鼠海马中的表达增加(p0.05),而多次氯胺酮给药后抑郁样大鼠海马Iba1、CD11b表达降低(p0.05)。4.CD11b阳性细胞数在建模成功后的抑郁样大鼠海马CA3区、DG区表达增加(p0.05),而多次氯胺酮给药后抑郁样大鼠海马CA3区、DG区CD11b阳性细胞数表达降低(p0.05)。结论1.将实验大鼠暴露在慢性不可以预见轻度应激环境中可导致抑郁样行为,而多次氯胺酮给药可将抑郁样症状改善。2.抑郁样大鼠海马中炎症细胞因子及小胶质细胞激活相关蛋白表达增加,而多次氯胺酮给药降低了炎症细胞因子及与小胶质细胞激活相关蛋白的表达。3.抑郁样大鼠海马中激活状态的小胶质细胞数量增加,而多次氯胺酮给药后激活状态的小胶质细胞数量减少。
[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- 伪, 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- 伪, IL-1 尾 and IL-6 in the hippocampus of depressive rats was increased (p0.05), and the expression of TNF- 伪, 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- 伪, 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.
【学位授予单位】：西南医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.4
本文编号：2278986
[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- 伪, 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- 伪, IL-1 尾 and IL-6 in the hippocampus of depressive rats was increased (p0.05), and the expression of TNF- 伪, 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- 伪, 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.
【学位授予单位】：西南医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.4
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相关期刊论文 前2条
1 Shangli Cai;Shucai Huang;Wei Hao;;New hypothesis and treatment targets of depression:an integrated view of key findings[J];Neuroscience Bulletin;2015年01期
2 张红,李永渝,王升年,张孔华,李丽娟,吴咸中;LPS-induced NF-κB activation requires Ca~2+ as a mediator in isolated pancreatic acinar cells of rat[J];Chinese Medical Journal;2003年11期
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