本文選題：氯胺酮 + 抗抑郁��； 參考：《南京大學(xué)》2012年碩士論文

【摘要】：目的：抑郁癥是全世界廣泛存存的影響人類身心健康的情緒障礙性疾病,發(fā)病率高達(dá)17%,是致殘的重要原因。近期人們發(fā)現(xiàn)氯胺酮作為一種非選擇性N-methyl-D-aspartate (NMDA)受體阻斷劑,治療抑郁癥可在2小時(shí)內(nèi)快速起效,效果長(zhǎng)達(dá)1周,且對(duì)難治性抑郁也有效果。盡管其抗抑郁機(jī)制尚未完全明確,但已有文獻(xiàn)證明哺乳動(dòng)物雷帕霉素靶蛋白通路(mammalian target of rapamycin, mTOR)可能在其中發(fā)揮了一定的作用。同時(shí),近期有實(shí)驗(yàn)證實(shí),糖原合成激酶3(glycogen synthesis kinase-3, GSK-3)對(duì)于氯胺酮發(fā)揮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機(jī)制中發(fā)揮何種作用尚不明確。因此,本研究的主要目的是觀察GSK-3在氯胺酮活化InTOR通路中發(fā)揮何種作用,以期進(jìn)一步揭示氯胺酮快速抗抑郁的具體機(jī)制,為研究新型抗抑郁藥提供新的思路和靶點(diǎn)。 方法：將30只Wistar大鼠分為5組,每組6只：Vehicle+Vehicle(V組)、Vehicle+氯胺酮組(K組)、PI3K/Akt抑制劑LY294002+氯胺酮組(L組)、mTOR抑制劑雷帕霉素+氯胺酮組(R組)、S6K抑制劑PF4708671+氯胺酮組(P組),測(cè)定大鼠前額皮層p-GSK-3β、p-mTOR和p-p70S6K表達(dá)水平。 結(jié)果：與V組相比,K組大鼠不動(dòng)時(shí)間減少(p0.05)；與K組相比,L組、R組和P組不動(dòng)時(shí)間顯著增加(尸0.05)。與V組相比,K組p-GSK3β表達(dá)水平增加；與K組相比,L組p-GSK3β水平降低(尸0.05),R組和P組無(wú)明顯變化(尸0.05)。與V組相比,K組p-mTOR及p-p70S6K顯著增加(尸0.05)；與K組相比,L組p-mTOR及p-p70S6K含量顯著降低(尸0.05),R組p-p70S6K含量降低(尸0.05)。 結(jié)論：小劑量氯胺酮可能通過(guò)激活PI3K/Akt來(lái)磷酸化GSK-3,繼而通過(guò)某種機(jī)制活化mTOI及其下游因子,開(kāi)啟突觸蛋白的轉(zhuǎn)錄,最終發(fā)揮抗抑郁作用。
[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.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.4

【共引文獻(xiàn)】

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