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

Abstract

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.

Intranasal (2R, 6R)‐hydroxynorketamine for acute pain: Behavioural and neurophysiological safety analysis in mice

“…Among various HNK metabolites characterized so far 14,16,17 ( 2 S, 6 S; 2R, 6R )‐HNK are reported abundantly in the brain and plasma of rodents 18–20 and also in human plasma 21 . Earlier classified as an inactive metabolite without any anaesthetic effects, 22 hydroxynorketamine has been explored for many biological functions in recent years 23–28 . Previous studies in mice have reported the analgesic and antidepressant effect of intraperitoneally injected ( 2R, 6R )‐HNK without sedative or addictive side effects 19,22,29 .…”

“…21 Earlier classified as an inactive metabolite without any anaesthetic effects, 22 hydroxynorketamine has been explored for many biological functions in recent years. [23][24][25][26][27][28] Previous studies in mice have reported the analgesic and antidepressant effect of intraperitoneally injected (2R, 6R)-HNK without sedative or addictive side effects. 19,22,29 Nevertheless, no study is available to document the efficacy and neurophysiological safety analysis of the intranasal dose of (2R, 6R)-HNK.…”

Crucial role of autophagy in propofol-treated neurological diseases: a comprehensive review

“…Electroshock therapy (ECT) is a method to treat depression by using a certain amount of current to pass through the brain to cause loss of consciousness and convulsions, to achieve the purpose of treatment ( Pagnin et al, 2004 ) However, ECT has some adverse reactions, such as headaches, nausea and vomiting, transient degenerative memory loss, and the impairment of learning and memory ( Pigot et al, 2008 ; Li et al, 2012 ). ECT has been found to be associated with neurotoxic injury ( Zhong et al, 2021 ). Recent studies have found that ECT may cause nervous system damage by inducing autophagy, and propofol can affect the nervous system by autophagy ( Otabe et al, 2014 ).…”