Abstract：
BACKGROUND: Post-traumatic stress disorder (PTSD) is a complex, chronic psychiatric disorder typically triggered by life-threatening events and, as yet, lacks a specialized pharmacological treatment. The potential therapeutic role of ketamine, an N-methyl-D-aspartate receptor antagonist, in mitigating PTSD has been the subject of investigation.
OBJECTIVE: The aim of this study was to elucidate alterations in the glycogen synthase kinase-3β (GSK-3β) signaling pathway in response to ketamine intervention, using the single prolonged stress (SPS) model of PTSD at a molecular level.
METHODS: PTSD-like symptoms were simulated using the SPS model. Ketamine (10 mg/kg) and GSK-3β antagonist SB216763 (5 mg/kg) were then administered intraperitoneally. Stress-related behavior was evaluated through the open field test (OFT) and the elevated plus maze test (EMPT). Additionally, brain activity was analyzed using quantitative electroencephalography (qEEG). Changes in protein and mRNA expressions of glucocorticoid receptor (GR), brain-derived neurotrophic factor (BDNF), GSK-3β, phosphorylated ser-9 GSK-3β (p-GSK-3β), FK506 binding protein 5 (FKBP5), and corticotropin-releasing hormone (CRH) were assessed in the hypothalamus via western blot and qPCR.
RESULTS: SPS-exposed rats exhibited reduced distance and time spent in the center of the open arms, a pattern divergent from control rats. qEEG readings revealed SPS-induced increases in alpha power, low gamma and high gamma power. Furthermore, SPS triggered an upregulation in the protein and gene expression of GSK-3β, GR, BDNF, p-GSK-3β, and FKBP5, and downregulated CRH expression in the hypothalamus. Ketamine administration following the SPS procedure counteracted these changes by increasing the time spent in the center of the OFT, the distance traversed in the open arms of the EMPT, and mitigating SPS-induced alterations in cerebral cortex oscillations. Moreover, ketamine reduced the protein levels of GSK-3β, GR, p-GSK-3β, and altered the ratio of p-GSK-3β to GSK-3β. Gene expression of GSK-3β, GR, BDNF, and FKBP5 decreased in the SPS-Ket group compared to the SPS-Sal group.
CONCLUSIONS: Ketamine appeared to remediate the abnormal GSK-3β signaling pathway induced by SPS. These findings collectively suggest that ketamine could be a promising therapeutic agent for PTSD symptoms, working through the modulation of the GSK-3β signaling pathway.
OBJECTIVE: The aim of this study was to elucidate alterations in the glycogen synthase kinase-3β (GSK-3β) signaling pathway in response to ketamine intervention, using the single prolonged stress (SPS) model of PTSD at a molecular level.
METHODS: PTSD-like symptoms were simulated using the SPS model. Ketamine (10 mg/kg) and GSK-3β antagonist SB216763 (5 mg/kg) were then administered intraperitoneally. Stress-related behavior was evaluated through the open field test (OFT) and the elevated plus maze test (EMPT). Additionally, brain activity was analyzed using quantitative electroencephalography (qEEG). Changes in protein and mRNA expressions of glucocorticoid receptor (GR), brain-derived neurotrophic factor (BDNF), GSK-3β, phosphorylated ser-9 GSK-3β (p-GSK-3β), FK506 binding protein 5 (FKBP5), and corticotropin-releasing hormone (CRH) were assessed in the hypothalamus via western blot and qPCR.
RESULTS: SPS-exposed rats exhibited reduced distance and time spent in the center of the open arms, a pattern divergent from control rats. qEEG readings revealed SPS-induced increases in alpha power, low gamma and high gamma power. Furthermore, SPS triggered an upregulation in the protein and gene expression of GSK-3β, GR, BDNF, p-GSK-3β, and FKBP5, and downregulated CRH expression in the hypothalamus. Ketamine administration following the SPS procedure counteracted these changes by increasing the time spent in the center of the OFT, the distance traversed in the open arms of the EMPT, and mitigating SPS-induced alterations in cerebral cortex oscillations. Moreover, ketamine reduced the protein levels of GSK-3β, GR, p-GSK-3β, and altered the ratio of p-GSK-3β to GSK-3β. Gene expression of GSK-3β, GR, BDNF, and FKBP5 decreased in the SPS-Ket group compared to the SPS-Sal group.
CONCLUSIONS: Ketamine appeared to remediate the abnormal GSK-3β signaling pathway induced by SPS. These findings collectively suggest that ketamine could be a promising therapeutic agent for PTSD symptoms, working through the modulation of the GSK-3β signaling pathway.
摘要：
背景：创伤后应激障碍（PTSD）是一种复杂的，慢性精神疾病通常由危及生命的事件引发，到目前为止，缺乏专门的药物治疗。氯胺酮的潜在治疗作用，一种N-甲基-D-天冬氨酸受体拮抗剂,减轻创伤后应激障碍一直是调查的主题。
目的：本研究的目的是阐明对氯胺酮干预的糖原合成酶激酶-3β（GSK-3β）信号通路的改变，在分子水平上使用PTSD的单一延长应激（SPS）模型。
方法：使用SPS模型模拟PTSD样症状。然后腹膜内给予氯胺酮(10mg/kg)和GSK-3β拮抗剂SB216763(5mg/kg)。通过开放场测试（OFT）和高架迷宫测试（EMPT）评估与应力相关的行为。此外,使用定量脑电图（qEEG）分析大脑活动。糖皮质激素受体(GR)蛋白和mRNA表达的变化,脑源性神经营养因子(BDNF),GSK-3β,磷酸化ser-9GSK-3β（p-GSK-3β），FK506结合蛋白5(FKBP5),通过蛋白质印迹和qPCR评估下丘脑中的促肾上腺皮质激素释放激素（CRH）。
结果：暴露于SPS的大鼠表现出在开放臂中心的距离和时间减少，与对照大鼠不同的模式。qEEG读数显示SPS诱导的α功率增加，低伽马和高伽马功率。此外，SPS引发GSK-3β蛋白和基因表达上调，GR,BDNF,p-GSK-3β,和FKBP5，并下调下丘脑中的CRH表达。SPS程序后的氯胺酮给药通过增加在OFT中心花费的时间来抵消这些变化，在EMPT的张开臂中穿过的距离，并减轻SPS诱导的大脑皮层振荡改变。此外，氯胺酮降低了GSK-3β的蛋白质水平，GR,p-GSK-3β,改变了p-GSK-3β与GSK-3β的比例。GSK-3β基因表达,GR,BDNF,与SPS-Sal组相比，SPS-Ket组的FKBP5降低。
结论：氯胺酮可修复SPS诱导的GSK-3β信号通路异常。这些发现共同表明氯胺酮可能是PTSD症状的有希望的治疗剂，通过调节GSK-3β信号通路。
目的：本研究的目的是阐明对氯胺酮干预的糖原合成酶激酶-3β（GSK-3β）信号通路的改变，在分子水平上使用PTSD的单一延长应激（SPS）模型。
方法：使用SPS模型模拟PTSD样症状。然后腹膜内给予氯胺酮(10mg/kg)和GSK-3β拮抗剂SB216763(5mg/kg)。通过开放场测试（OFT）和高架迷宫测试（EMPT）评估与应力相关的行为。此外,使用定量脑电图（qEEG）分析大脑活动。糖皮质激素受体(GR)蛋白和mRNA表达的变化,脑源性神经营养因子(BDNF),GSK-3β,磷酸化ser-9GSK-3β（p-GSK-3β），FK506结合蛋白5(FKBP5),通过蛋白质印迹和qPCR评估下丘脑中的促肾上腺皮质激素释放激素（CRH）。
结果：暴露于SPS的大鼠表现出在开放臂中心的距离和时间减少，与对照大鼠不同的模式。qEEG读数显示SPS诱导的α功率增加，低伽马和高伽马功率。此外，SPS引发GSK-3β蛋白和基因表达上调，GR,BDNF,p-GSK-3β,和FKBP5，并下调下丘脑中的CRH表达。SPS程序后的氯胺酮给药通过增加在OFT中心花费的时间来抵消这些变化，在EMPT的张开臂中穿过的距离，并减轻SPS诱导的大脑皮层振荡改变。此外，氯胺酮降低了GSK-3β的蛋白质水平，GR,p-GSK-3β,改变了p-GSK-3β与GSK-3β的比例。GSK-3β基因表达,GR,BDNF,与SPS-Sal组相比，SPS-Ket组的FKBP5降低。
结论：氯胺酮可修复SPS诱导的GSK-3β信号通路异常。这些发现共同表明氯胺酮可能是PTSD症状的有希望的治疗剂，通过调节GSK-3β信号通路。
