Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China.
Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, PR China.
J Affect Disord. 2025 Jan 1;368:282-294. doi: 10.1016/j.jad.2024.08.123. Epub 2024 Sep 10.
Neuron excitotoxic damage induced by extracellular glutamate accumulation pathologically is one of the main mechanisms of depression. Glutamate transporter-1 (GLT-1) expressed in astrocyte is responsible for glutamate clearance to maintain glutamate balance. Electroconvulsive therapy (ECT) is prevalently recommended for severe depression due to its significant anti-depressant effect. Esketamine could offer advantages of rapid anti-depressant effect and neuron protection. The aim of this study is to investigate the anti-depressant efficacy of esketamine plus ECT, and further to explore the mechanism. Firstly, total 12 patients were randomized into anesthesia with propofol (P) or propofol+esketamine (PK) before ECT. 24-Hamilton Depression Scale (HAMD) was used to evaluate the severity of depression after each ECT. Then, depressive rat model was built using chronic unpredictable mild stress method, and subsequently received infusion of esketamine (5 mg/kg) or saline before ECT treatment (0.5 mA; 100 V) for consecutive 10 days. Tests including sucrose preference test, open field test and forced swimming test were used to evaluate depression-like behaviors. In next experiments, rats were injected with RIL, DHK or LY294002 intracerebroventricularly for continuous 10 days before individual treatment. After the fifth and sixth ECT, PK group displayed lower HAMD score compared to P group. In rat model, we found that esketamine plus ECT could significantly improve depression-like behaviors and decrease glutamate level. Esketamine and ECT could both activate PI3K/Akt/GLT-1 pathway. The GLT-1 agonist RIL made equivalent effect as esketamine plus ECT. Furthermore, after using PI3K/Akt inhibitor LY294002 and GLT-1 inhibitor DHK, esketamine plus ECT could neither improve depression-like symptoms, nor upregulate GLT-1 level. Our present study suggested that esketamine plus ECT could dramatically improve depression symptom. The activation of PI3K/Akt/GLT-1 pathway may be the potential mechanism.
细胞外谷氨酸积累导致的神经元兴奋性毒性损伤是抑郁症的主要机制之一。星形胶质细胞表达的谷氨酸转运体-1（GLT-1）负责清除谷氨酸以维持谷氨酸平衡。由于电休克疗法（ECT）具有显著的抗抑郁作用，因此被广泛推荐用于重度抑郁症。氯胺酮可以提供快速抗抑郁作用和神经元保护的优势。本研究旨在探讨氯胺酮联合 ECT 的抗抑郁疗效，并进一步探讨其机制。首先，将 12 名患者随机分为丙泊酚（P）麻醉或丙泊酚+氯胺酮（PK）麻醉组，然后在 ECT 前后使用 24 小时汉密尔顿抑郁量表（HAMD）评估抑郁严重程度。随后，采用慢性不可预测轻度应激法建立抑郁大鼠模型，随后在 ECT 治疗前（0.5 mA；100 V）输注氯胺酮（5 mg/kg）或生理盐水，连续 10 天。采用蔗糖偏好试验、旷场试验和强迫游泳试验评估抑郁样行为。在接下来的实验中，大鼠连续 10 天接受 RIL、DHK 或 LY294002 脑室内注射，然后进行单独治疗。在第五和第六次 ECT 后，PK 组的 HAMD 评分明显低于 P 组。在大鼠模型中，我们发现氯胺酮联合 ECT 可显著改善抑郁样行为，降低谷氨酸水平。氯胺酮和 ECT 均可激活 PI3K/Akt/GLT-1 通路。GLT-1 激动剂 RIL 与氯胺酮联合 ECT 具有相同的作用。此外，使用 PI3K/Akt 抑制剂 LY294002 和 GLT-1 抑制剂 DHK 后，氯胺酮联合 ECT 既不能改善抑郁症状，也不能上调 GLT-1 水平。本研究表明，氯胺酮联合 ECT 可显著改善抑郁症状。PI3K/Akt/GLT-1 通路的激活可能是潜在的机制。
