Propofol prevents electroconvulsive-shock-induced memory impairment through regulation of hippocampal synaptic plasticity in a rat model of depression

Abstract

BackgroundAlthough a rapid and efficient psychiatric treatment, electroconvulsive therapy (ECT) induces memory impairment. Modified ECT requires anesthesia for safety purposes. Although traditionally found to exert amnesic effects in general anesthesia, which is an inherent part of modified ECT, some anesthetics have been found to protect against ECT-induced cognitive impairment. However, the mechanisms remain unclear. We investigated the effects of propofol (2,6-diisopropylphenol) on memory in depressed rats undergoing electroconvulsive shock (ECS), the analog of ECT in animals, under anesthesia as well as its mechanisms.MethodsChronic unpredictable mild stresses were adopted to reproduce depression in a rodent model. Rats underwent ECS (or sham ECS) with anesthesia with propofol or normal saline. Behavior was assessed in sucrose preference, open field and Morris water maze tests. Hippocampal long-term potentiation (LTP) was measured using electrophysiological techniques. PSD-95, CREB, and p-CREB protein expression was assayed with Western blotting.ResultsDepression induced memory damage, and downregulated LTP, PSD-95, CREB, and p-CREB; these effects were exacerbated in depressed rats by ECS; propofol did not reverse the depression-induced changes, but when administered in modified ECS, propofol improved memory and reversed the downregulation of LTP and the proteins.ConclusionThese findings suggest that propofol prevents ECS-induced memory impairment, and modified ECS under anesthesia with propofol improves memory in depressed rats, possibly by reversing the excessive changes in hippocampal synaptic plasticity. These observations provide a novel insight into potential targets for optimizing the clinical use of ECT for psychiatric disorders.

Cognitive functioning in patients treated with electroconvulsive therapy

“… 37 We did not find a difference between anesthetics used in regard to cognitive side effects, since some studies prefer propofol. 26 , 38 …”

Effects of Electroconvulsive Therapy on Depression and Its Potential Mechanism

“…Moreover, contrary to other CUMS cognitive performance, ECS improved memory function in CUMS compared with the baseline cognitive index (Luo et al, 2015). However, ECS under anesthesia with propofol, dexmedetomidine, or ketamine was able to rescue ECS-exacerbated dysfunction to improve memory performance (Luo et al, 2011(Luo et al, , 2014Zhu et al, 2015a,b;Gao et al, 2016;Zhang et al, 2016). In spite of the effectiveness of anesthesia plus ECS in enhancing cognitive performance without undermining ECS effectiveness, modified ECT caused less cognitive concern in clinical studies, and even older depressed patients with cognitive decline retrieved memory after undergoing ECT (Osler et al, 2018;Socci et al, 2018).…”

“…Behavioral analysis was recorded to demonstrate depressing activities in animal models and behavioral changes after undergoing ECS. Rats treated with chronic unpredictable mild stress (CUMS), which caused them to display depression-like behavior, exhibited decreased sucrose preference percentage (SPP) and impaired performance on the open field test (OFT), forced swim test, novelty suppressed feeding test (NSF), and Morris water maze, and ECS inversely increased SPP and OFT activities (Luo et al, 2011(Luo et al, , 2014Zhu et al, 2015a,b;Gao et al, 2016;Zhang et al, 2016). Similarly, in the Wistar-Kyoto (WKY) rat strain, a genetic model displaying depression-and anxietylike behaviors and working memory deficit, ECS improved psychiatric and memory behaviors (Kyeremanteng et al, 2014).…”

“…With respect to cognitive performance, based on the CUMS animal models that reproduced depression, ECS deteriorated cognitive performance in animal models via (1) downregulating the ratio of hippocampal glutamate (Glu) and γ-aminobutyric acid (GABA) levels by promoting excessive expression of glutamic acid decarboxylase 65 (GAD65) (Luo et al, 2011); (2) dysregulating hippocampal synaptic plasticity, specifically downregulating long-term potentiation (LTP), postsynaptic density-95 (PSD-95), and phospho-response element binding protein (p-CREB) protein expression (Luo et al, 2014); (3) inducing inflammatory cytokine-mediated glutamate uptake dysfunction in the hippocampus (Zhu et al, 2015a); (4) promoting neuroinflammation and increasing the levels of Aβ1-40 and Aβ1-42 in the hippocampus (Zhu et al, 2015b); (5) dysregulating the NMDA receptor subunit 2B (NR2B)-(extracellular signal-regulate kinase) ERKsignaling pathway (Gao et al, 2016); and (6) up-regulating the ratio of the precursor of brain-derived neurotrophic factor (proBDNF)/mature BDNF (mBDNF) (Zhang et al, 2016). However, ECS caused different memory indexes between types of animal models (Luo et al, 2015).…”

Mouse repeated electroconvulsive seizure (ECS) does not reverse social stress effects but does induce behavioral and hippocampal changes relevant to electroconvulsive therapy (ECT) side-effects in the treatment of depression

“…For example, ECS-induced reductions in depression-like behavior were found to be accompanied by normalization of BDNF and Neuropeptide Y expression in brain areas relevant to depression [ 27 – 30 ]. Other studies have focused on the mechanisms involved in ECS-induced memory impairment, with results pointing towards increased HPA-axis activity and decreased long-term potentiation as underlying factors [ 27 , 29 ]. Interestingly, memory-related side effects could be prevented by pre-treatment with propofol without affecting antidepressant effects, provided that ECS stimulus intensity was increased in propofol-treated rats, demonstrating the importance of performing ECS studies under clinically relevant conditions [ 29 ].…”