中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (1): 128-135.doi: 10.4103/1673-5374.264466

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

GLYX-13预处理可成为治疗麻醉诱导认知障碍的潜在方法？

  

  • 出版日期:2020-01-15 发布日期:2020-05-20
  • 基金资助:

    国家自然科学基金项目（81730033，81701371，81801380）；江苏省自然科学基金项目（BK20170654，BK20170129）

GLYX-13 pretreatment ameliorates long-term isoflurane exposure-induced cognitive impairment in mice

Huan Liu1, Xiang-Dan Gong1, Xin Zhao1, Yue Qian1, Xiao-Ping Gu1, Tian-Jiao Xia1, 2   

  1. 1 Department of Anesthesiology, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
    2 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
  • Online:2020-01-15 Published:2020-05-20
  • Contact: Xiao-Ping Gu, PhD,xiaopinggu@nju.edu.cn;Tian-Jiao Xia, PhD,tjxia@nju.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81730033 (to XPG), 81701371 (to TJX), 81801380 (to XZ) and Natural Science Foundation of Jiangsu Province of China, No. BK20170654 (to TJX), BK20170129 (to XZ).

PDF

164

摘要：

异氟醚长期吸入会增加认知障碍发生的危险。GLYX-13可作用于N-甲基-D-天冬氨酸受体的甘氨酸位点，并可增强海马依赖性学习和记忆功能，但其具体机制尚不明确。实验设计方案为：(1)以1.5％异氟烷暴露6h建立长期异氟醚麻醉暴露小鼠模型，麻醉前2h静脉注射1mg/kg GLYX-13。以应用情境恐惧条件反射测试和新物体识别试验来评估认知功能，以定量PCR和Western blot评估海马中NR2B-CaMKII-CREB信号传导通路相关蛋白NR2B，CaMKII和CREB的mRNA表达和磷酸化蛋白表达的情况。结果显示，GLYX-13能明显减轻长期异氟醚麻醉诱导小鼠的认知功能障碍，恢复NR2B，CaMKII和CREB mRNA表达和磷酸化蛋白表达；(2)在异氟醚暴露前4h侧脑室注射1μL的选择性钙离子-钙调素依赖性蛋白激酶II 抑制剂KN93（1mM）后，GLYX-13对认知功能以及海马中NR2B-CaMKII-CREB信号传导通路相关蛋白mRNA表达和磷酸化蛋白表达的作用明显受到抑制；(3)结果提示GLYX-13预处理通过调节海马NR2B-CaMKII-CREB信号通路，对异氟醚诱导的认知功能障碍起到保护作用，这可能成为治疗麻醉诱导认知障碍的潜在方法。实验于2017年11月20日经南京大学医学院附属鼓楼医院实验动物伦理委员会批准，批准号20171102。

orcid: 0000-0002-8218-7299 (Xiao-Ping Gu)

关键词: 异氟醚, GLYX-13, N-甲基-D-天冬氨酸受体, 钙离子-钙调素依赖性蛋白激酶II, CREB, 认知障碍, 情境恐惧条件反射测试, 新物体识别试验

Abstract:

Accumulating evidence indicates that inhalation anesthetics induce or increase the risk of cognitive impairment. GLYX-13 (rapastinel) acts on the glycine site of N-methyl-D-aspartate receptors (NMDARs) and has been shown to enhance hippocampus-dependent learning and memory function. However, the mechanisms by which GLYX-13 affects learning and memory function are still unclear. In this study, we investigated these mechanisms in a mouse model of long-term anesthesia exposure. Mice were intravenously administered 1 mg/kg GLYX-13 at 2 hours before isoflurane exposure (1.5% for 6 hours). Cognitive function was assessed using the contextual fear conditioning test and the novel object recognition test. The mRNA expression and phosphorylated protein levels of NMDAR pathway components, N-methyl-D-aspartate receptor subunit 2B(NR2B)-Ca2+/calmodulin dependent protein kinase II (CaMKII)-cyclic adenosine monophosphate response element binding protein (CREB), in the hippocampus were evaluated by quantitative RT-PCR and western blot assay. Pretreatment with GLYX-13 ameliorated isoflurane exposure-induced cognitive impairment and restored NR2B, CaMKII and CREB mRNA and phosphorylated protein levels. Intracerebroventricular injection of KN93, a selective CaMKII inhibitor, significantly diminished the effect of GLYX-13 on cognitive function and NR2B, CaMKII and CREB levels in the hippocampus. Taken together, our findings suggest that GLYX-13 pretreatment alleviates isoflurane-induced cognitive dysfunction by protecting against perturbation of the NR2B/CaMKII/CREB signaling pathway in the hippocampus. Therefore, GLYX-13 may have therapeutic potential for the treatment of anesthesia-induced cognitive dysfunction. This study was approved by the Experimental Animal Ethics Committee of Drum Tower Hospital affiliated to the Medical College of Nanjing University, China (approval No. 20171102) on November 20, 2017.

Key words: Ca2+/calmodulin-dependent protein kinase II, cognitive impairment, contextual fear conditioning, cyclic adenosine monophosphate response element binding protein, GLYX-13, isoflurane, N-methyl-D-aspartate receptor, novel object recognition, rapastinel