(2R,6R)-羟基去甲氯胺酮通过抑制自噬减轻电休克诱导的学习障碍。
(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy.
作者信息
Zhong Xiaomei, Ouyang Cong, Liang Wanyuan, Dai Cunying, Zhang Weiru
机构信息
Department of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People's Republic of China.
Institute of Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People's Republic of China.
出版信息
Neuropsychiatr Dis Treat. 2021 Feb 3;17:297-304. doi: 10.2147/NDT.S278422. eCollection 2021.
PURPOSE
Learning impairment after electroconvulsive therapy (ECT) is common. Ketamine, an anesthetic used for ECT, has been demonstrated to attenuate cognitive impairment after ECT. However, the mechanism by which ketamine occurs in this case is still unknown. We aimed to explore the role of ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] in the protection against learning impairment and investigate whether autophagy is involved in the protective effect.
MATERIALS AND METHODS
A rat depression model received electroconvulsive shock (ECS; simulated ECT in animal models) daily for 3 days. The Morris water maze was used to assess the spatial learning function of the rats. Western blotting was used to detect the expression of Beclin-1, light chain (LC)3-II/LC3-I, p62, mammalian target of rapamycin (mTOR), and p-mTOR in the hippocampus.
RESULTS
The escape latency for the maze in the ECS group was significantly longer than that in the sham ECS group (P=0.042). Meanwhile, the escape latency in the (2R,6R)-HNK+ECS group was significantly shorter than that in the ECS group (P=0.005). The LC3-II/LC3-I ratio and Beclin-1 expression level significantly increased, and the p62 expression level significantly decreased in the ECS group, compared with those in the sham ECS group (all P<0.001). The (2R,6R)-HNK+ECS group showed lower LC3-II/LC3-I ratio (P<0.001) and Beclin-1 expression level (P<0.001) and higher p62 (P<0.001) and p-mTOR expression levels (P=0.048) than did the ECS group. After small-molecule enhancer of rapamycin 28 (SMER28) administration, the role of (2R,6R)-HNK in protecting against learning impairment and inhibiting autophagy was abrogated, showing no difference in the escape latency; the difference in the LC3-II/LC3-I ratio and p62 expression level between the SMER28+(2R,6R)-HNK+ECS and ECS groups was not as significant as that between the (2R,6R)-HNK+ECS and ECS groups (P<0.05-0.01 vs P<0.001).
CONCLUSION
(2R,6R)-HNK yields cognitive protection by suppressing autophagy through the mTOR signaling pathway in the ECS-treated rat hippocampus.
目的
电休克治疗（ECT）后出现学习障碍很常见。氯胺酮是一种用于ECT的麻醉剂，已被证明可减轻ECT后的认知障碍。然而，氯胺酮在这种情况下发挥作用的机制仍不清楚。我们旨在探讨氯胺酮代谢物（2R,6R）-羟基去甲氯胺酮[（2R,6R）-HNK]在预防学习障碍中的作用，并研究自噬是否参与其保护作用。
材料与方法
将大鼠抑郁模型每日接受电休克（ECS；动物模型中的模拟ECT），持续3天。采用莫里斯水迷宫评估大鼠的空间学习功能。采用蛋白质免疫印迹法检测海马中Beclin-1、轻链（LC）3-II/LC3-I、p62、哺乳动物雷帕霉素靶蛋白（mTOR）和p-mTOR的表达。
结果
ECS组迷宫逃避潜伏期显著长于假ECS组（P=0.042）。同时，（2R,6R）-HNK+ECS组的逃避潜伏期显著短于ECS组（P=0.005）。与假ECS组相比，ECS组的LC3-II/LC3-I比值和Beclin-1表达水平显著升高，p62表达水平显著降低（均P<0.001）。与ECS组相比，（2R,6R）-HNK+ECS组的LC3-II/LC3-I比值（P<0.001）和Beclin-1表达水平（P<0.001）较低，p62（P<0.001）和p-mTOR表达水平较高（P=0.048）。给予雷帕霉素小分子增强剂28（SMER28）后，（2R,6R）-HNK在预防学习障碍和抑制自噬方面的作用被消除，逃避潜伏期无差异；SMER28+（2R,6R）-HNK+ECS组与ECS组之间LC3-II/LC3-I比值和p62表达水平的差异不如（2R,6R）-HNK+ECS组与ECS组之间显著（P<0.05-0.01 vs P<0.001）。
结论
在接受ECS治疗的大鼠海马中，（2R,6R）-HNK通过mTOR信号通路抑制自噬产生认知保护作用。
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