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(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy

Authors Zhong X, Ouyang C, Liang W, Dai C, Zhang W

Received 25 August 2020

Accepted for publication 11 January 2021

Published 3 February 2021 Volume 2021:17 Pages 297—304

DOI https://doi.org/10.2147/NDT.S278422

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Yuping Ning


Xiaomei Zhong,1 Cong Ouyang,2 Wanyuan Liang,2 Cunying Dai,2 Weiru Zhang2

1Department of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of China; 2Institute of Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of China

Correspondence: Xiaomei Zhong
Department of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of China
Tel +8620-8126-8084
Fax +8620-8189-1391
Email lovlaugh@163.com

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.

Keywords: electroconvulsive shock, learning impairment, (2R 6R)-hydroxynorketamine, autophagy

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