酰米菲肽抗抑郁作用及其机制初步研究

发布时间：2018-04-21 09:01

本文选题：酰米菲肽 + 抗抑郁　；参考：《中国人民解放军医学院》2014年硕士论文

【摘要】：目的：评价酰米菲肽（代号：XMT）的抗抑郁作用，初步研究其可能的作用机制。方法：1、采用小鼠行为绝望模型（小鼠悬尾实验、小鼠强迫游泳实验）和大鼠慢性不可预测性温和应激（CUMS）抑郁模型评价酰米菲肽的抗抑郁作用。2、采用药物诱发行为药理学模型（5-羟色氨酸诱导甩头实验、育亨宾毒性增强实验）和高效液相色谱-电化学检测法（HPLC-ECD）测定大鼠大脑前额皮层单胺神经递质及其代谢产物的含量，从中枢单胺系统水平研究酰米菲肽的抗抑郁作用机制。3、采用酶联免疫法（ELISA）测定大鼠血清促肾上腺皮质激素（ACTH）和皮质酮（CORT）含量，从下丘脑-垂体-肾上腺素（HPA）轴水平探究酰米菲肽的抗抑郁作用机制。4、采用Morris水迷宫实验评价酰米菲肽对大鼠空间学习记忆能力的影响。结果：1、悬尾实验和强迫游泳实验中，酰米菲肽可分别显著缩短小鼠的悬尾和游泳不动时间；在有效剂量范围内，酰米菲肽对小鼠的自发活动没有影响，排除了中枢兴奋剂对实验结果产生假阳性的干扰。以上实验结果表明，酰米菲肽在小鼠行为绝望模型中具有一定的抗抑郁作用。2、酰米菲肽可显著提高CUMS抑郁模型大鼠的糖水偏嗜度、旷场实验的水平和垂直运动得分、并可显著改善抑郁模型大鼠体重增长减慢的现象。以上实验结果表明，酰米菲肽可显著缓解CUMS抑郁模型大鼠的快感缺失、活动量减少、兴趣缺乏、体重增加缓慢等抑郁样行为，具有良好的抗抑郁作用。3、5-HTP诱导小鼠甩头实验中，酰米菲肽可显著减少5-HTP诱导的甩头行为，而在育亨宾毒性增强实验中，酰米菲肽对育亨宾的毒性没有明显增强作用，提示酰米菲肽的抗抑郁作用可能与中枢5-HT能系统相关。4、酰米菲肽可不同程度提高CUMS抑郁模型大鼠前额皮层区5-HT、DA含量，并且显著提高前额皮层区5-HT/5-HIAA和DA/DOPAC的比值，，降低5-HT和DA在脑内的转化率，提示酰米菲肽的抗抑郁作用可能与抑制单胺氧化酶相关。5、酰米菲肽可显著降低CUMS抑郁模型大鼠血清ACTH和CORT水平，提示酰米菲肽的抗抑郁作用可能与抑制HPA轴功能亢进相关。6、Morris水迷宫实验中，酰米菲肽可明显提高大鼠穿越平台所在位置的次数、平台所在象限停留的时间和移动路程，表明酰米菲肽具有改善CUMS造成大鼠认知功能损伤的作用。结论：1、酰米菲肽在小鼠行为绝望模型和大鼠CUMS抑郁模型中具有一定的抗抑郁作用。2、酰米菲肽抗抑郁作用机制可能与中枢5-HT能系统、HPA轴等多种途径相关。3、酰米菲肽可改善CUMS抑郁模型大鼠的空间学习记忆能力障碍。
[Abstract]:Aim: to evaluate the antidepressant effect of acyl miffy peptide (XMTA) and to study its possible mechanism. Methods: 1. The mouse behavioral despair model (mouse tail suspension test) was used. The antidepressant effect of acyl miffy peptide was evaluated in rats with chronic unpredictability mild stress (CUMS) and forced swimming in mice. The pharmacological model of drug-induced behavior was used to induce head flick induced by 5-hydroxytryptophan. The contents of monoamine neurotransmitters and their metabolites in the prefrontal cortex of rats were determined by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The antidepressant mechanism of acyl miffy peptide was studied at the level of central monoamine system. The levels of serum adrenocorticotropic hormone (ACTH) and corticosterone (Cort) were measured by enzyme linked immunosorbent assay (Elisa). The antidepressant mechanism of acyl miffy peptide was investigated by using hypothalamus-pituitary-adrenaline (HPA) axis. The effects of acyl miffy peptide on spatial learning and memory in rats were evaluated by Morris water maze test. Results: in the tail suspension test and forced swimming test, Acyl miffy peptide significantly shortened the tail suspension and swimming immobility time of mice, but in the effective dose range, the acyl miffy peptide had no effect on the spontaneous activity of mice. The effect of central stimulant on the false positive results was excluded. The results showed that Acyl miffy peptide had a certain antidepressant effect in the behavioral despair model of mice. Acyl miffy peptide could significantly increase the degree of preference of sugar and water and the scores of horizontal and vertical motion of open field test in CUMS depression model rats. And can significantly improve the depression model rats weight growth slow down phenomenon. The results showed that Acyl miffy peptide could significantly alleviate the depression-like behaviors such as loss of pleasure, decreased activity, lack of interest, slow weight gain and so on, and had a good antidepressant effect. Acyl miffy peptide could significantly reduce the head flick behavior induced by 5-HTP, but in yohimbine toxicity enhancement test, the toxicity of acyl miffy peptide to yohimbine was not significantly enhanced. It is suggested that the antidepressant effect of acyl miffy peptide may be related to the central 5-HT energy system. Acyl miffy peptide can increase the content of 5-HTDA in the prefrontal cortex and the ratio of 5-HT/5-HIAA to DA/DOPAC in the prefrontal cortex of CUMS depression model rats. The decrease of the conversion rate of 5-HT and DA in brain suggests that the antidepressant effect of acyl miffy peptide may be related to the inhibition of monoamine oxidase. Acyl miffy peptide can significantly reduce the levels of serum ACTH and CORT in rats with CUMS depression. It is suggested that the antidepressant effect of acyl miffy peptide may be related to the inhibition of hyperfunction of HPA axis. In the Morris water maze experiment, the number of times of crossing the platform, the time of staying in the quadrant and the distance of movement of the platform were significantly increased. The results suggest that the acyl miffy peptide can improve the cognitive impairment induced by CUMS in rats. Conclusion: 1, Acyl miffy peptide has antidepressant effect in mouse behavioral despair model and rat CUMS depression model. The antidepressant mechanism of acyl miffy peptide may be related to several pathways, such as central 5-HT energy system, CUMS axis, etc., and acyl miffy peptide may be related to the antidepressant effect of Acyl miffy peptide. It can improve the ability of spatial learning and memory in CUMS depression model rats.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

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