糖原合成激酶3在氯胺酮活化mTOR通路中发挥的作用

发布时间：2018-07-03 16:39

本文选题：氯胺酮 + 抗抑郁　；参考：《南京大学》2012年硕士论文

【摘要】：目的：抑郁症是全世界广泛存存的影响人类身心健康的情绪障碍性疾病,发病率高达17%,是致残的重要原因。近期人们发现氯胺酮作为一种非选择性N-methyl-D-aspartate (NMDA)受体阻断剂,治疗抑郁症可在2小时内快速起效,效果长达1周,且对难治性抑郁也有效果。尽管其抗抑郁机制尚未完全明确,但已有文献证明哺乳动物雷帕霉素靶蛋白通路(mammalian target of rapamycin, mTOR)可能在其中发挥了一定的作用。同时,近期有实验证实,糖原合成激酶3(glycogen synthesis kinase-3, GSK-3)对于氯胺酮发挥快速抗抑郁作用也是必需的,然而GSK-3到底在氯胺酮抗抑郁机制中发挥何种作用尚不明确。因此,本研究的主要目的是观察GSK-3在氯胺酮活化InTOR通路中发挥何种作用,以期进一步揭示氯胺酮快速抗抑郁的具体机制,为研究新型抗抑郁药提供新的思路和靶点。方法：将30只Wistar大鼠分为5组,每组6只：Vehicle+Vehicle(V组)、Vehicle+氯胺酮组(K组)、PI3K/Akt抑制剂LY294002+氯胺酮组(L组)、mTOR抑制剂雷帕霉素+氯胺酮组(R组)、S6K抑制剂PF4708671+氯胺酮组(P组),测定大鼠前额皮层p-GSK-3β、p-mTOR和p-p70S6K表达水平。结果：与V组相比,K组大鼠不动时间减少(p0.05)；与K组相比,L组、R组和P组不动时间显著增加(尸0.05)。与V组相比,K组p-GSK3β表达水平增加；与K组相比,L组p-GSK3β水平降低(尸0.05),R组和P组无明显变化(尸0.05)。与V组相比,K组p-mTOR及p-p70S6K显著增加(尸0.05)；与K组相比,L组p-mTOR及p-p70S6K含量显著降低(尸0.05),R组p-p70S6K含量降低(尸0.05)。结论：小剂量氯胺酮可能通过激活PI3K/Akt来磷酸化GSK-3,继而通过某种机制活化mTOI及其下游因子,开启突触蛋白的转录,最终发挥抗抑郁作用。
[Abstract]:Objective: depression is an emotional disorder that affects human physical and mental health widely in the world. The incidence of depression is as high as 17, and it is an important cause of disability. As a nonselective N-methyl-D-aspartate (NMDA) receptor blocker, ketamine has been found to be effective in the treatment of depression for up to one week in 2 hours. Although its antidepressant mechanism has not been fully understood, it has been shown that the mammalian rapamycin target protein pathway (mammalian target of rapamycin, mTOR may play a role in it. At the same time, recent experiments have confirmed that glycogen synthetic kinase 3 (glycogen synthesis kinase-3 (GSK-3) is necessary for ketamine to play a rapid antidepressant effect. However, it is not clear what role GSK-3 plays in ketamine antidepressant mechanism. Therefore, the main purpose of this study was to investigate the role of GSK-3 in the activation of InTOR pathway by ketamine in order to further reveal the specific mechanism of rapid antidepressant by ketamine, and to provide new ideas and targets for the study of new antidepressants. Methods: thirty Wistar rats were divided into 5 groups. The expression of GSK-3 尾 -p-mTOR and p-p70S6K in prefrontal cortex of rats were measured in each group (group V): vehicle ketamine group (group K), LY294002 Ketamine group (group L), rapamycin ketamine group (group R), rapamycin ketamine group (group R) and PF4708671 ketamine group (group P). Results: compared with group V, the immobility time of rats in group K decreased (p0.05), and the time of immobility in group R and group P increased significantly compared with group K (P 0.05). Compared with group V, the expression of p-GSK3 尾 increased in group K, but the level of p-GSK3 尾 decreased in group C (P 0.05), group R (0.05) and group P (0.05). Compared with group V, p-mTOR and p-p70S6K were significantly increased (P < 0.05), and the contents of p-mTOR and p-p70S6K were significantly decreased (P < 0.05) in group K and P -mTOR and p-p70S6K in group R (P < 0.05). Conclusion: low dose ketamine may phosphorylate GSK-3 by activating PI3K / Akt, and then activate mTOI and its downstream factors through some mechanism, which may turn on the transcription of synaptic protein and ultimately play an antidepressant role.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.4

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