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

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 o...

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Autores principales:	Zhong X, Ouyang C, Liang W, Dai C, Zhang W
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	electroconvulsive shock learning impairment (2r 6r)-hydroxynorketamine autophagy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/124324d425004ccb8a8e8524ea67aaa9
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spelling	oai:doaj.org-article:124324d425004ccb8a8e8524ea67aaa92021-12-02T14:24:09Z(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy1178-2021https://doaj.org/article/124324d425004ccb8a8e8524ea67aaa92021-02-01T00:00:00Zhttps://www.dovepress.com/2r6r-hydroxynorketamine-alleviates-electroconvulsive-shock-induced-lea-peer-reviewed-article-NDThttps://doaj.org/toc/1178-2021Xiaomei 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 ChinaCorrespondence: Xiaomei ZhongDepartment of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of ChinaTel +8620-8126-8084Fax +8620-8189-1391Email lovlaugh@163.comPurpose: 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, autophagyZhong XOuyang CLiang WDai CZhang WDove Medical Pressarticleelectroconvulsive shocklearning impairment(2r6r)-hydroxynorketamineautophagyNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol Volume 17, Pp 297-304 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	electroconvulsive shock learning impairment (2r 6r)-hydroxynorketamine autophagy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	electroconvulsive shock learning impairment (2r 6r)-hydroxynorketamine autophagy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Zhong X Ouyang C Liang W Dai C Zhang W (2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy
description	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 ChinaCorrespondence: Xiaomei ZhongDepartment of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of ChinaTel +8620-8126-8084Fax +8620-8189-1391Email lovlaugh@163.comPurpose: 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
format	article
author	Zhong X Ouyang C Liang W Dai C Zhang W
author_facet	Zhong X Ouyang C Liang W Dai C Zhang W
author_sort	Zhong X
title	(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy
title_short	(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy
title_full	(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy
title_fullStr	(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy
title_full_unstemmed	(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy
title_sort	(2r,6r)-hydroxynorketamine alleviates electroconvulsive shock-induced learning impairment by inhibiting autophagy
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/124324d425004ccb8a8e8524ea67aaa9
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(2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy

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