中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (6): 1029-1036.doi: 10.4103/1673-5374.250621

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

α5GABAA受体抑制对异氟醚诱导的老年大鼠认知障碍仅具有预防作用

  

  • 出版日期:2019-06-15 发布日期:2019-06-15

Inhibition of α5 GABAA receptors has preventive but not therapeutic effects on isoflurane-induced memory impairment in aged rats

Zi-Fang Zhao 1 , Lei Du 2 , Teng Gao 3 , Lin Bao 1 , Yuan Luo 4 , Yi-Qing Yin 1 , Yong-An Wang 4   

  1. 1 Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China
    2Department of Radiology, China-Japan Friendship Hospital, Beijing, China
    3 Department of Anesthesiology, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing, China
    4 Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, China
  • Online:2019-06-15 Published:2019-06-15
  • Contact: Yi-Qing Yin, M.D., yyq518@sina.com; Yong-An Wang, M.D., yonganw@126.com.

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摘要：

γ-氨基丁酸A型受体α5亚单位（α5 subunit-containing gamma-amino butyric acid type A receptors, α5 GABAARs）相对特异性地分布在哺乳动物的海马脑区，也是海马神经元tonic抑制电流的调控受体。研究发现低浓度的异氟烷可以增强tonic电流，该效应会导致小鼠出现空间学习记忆功能受损。而α5 GABAAR的反向激动剂（如L-655,708）可以逆转青年小鼠低浓度异氟烷麻醉后出现的学习记忆损害，但α5 GABAAR的负向变构调节剂对于老年动物是否仍有上述效应目前尚不明确。实验主要探究L-655,708对于低浓度异氟烷（1.3%）麻醉引起的老年动物空间学习记忆损害是否有改善作用。选用3月龄（青年）和24月龄（老年）的Wistar大鼠为研究对象，分别在1.3%的异氟烷麻醉前0.5 h或麻醉后23.5 h予以L-655,708皮下注射。Morris水迷宫实验发现，在麻醉前或者麻醉后皮下注射L-655,708可以逆转1.3%浓度的异氟烷所致的青年大鼠空间学习记忆损害，而对老年大鼠则只有在麻醉前给药有类似作用。RT-PCR结果提示，低浓度异氟烷麻醉后老年大鼠海马神经元α5 GABAAR的mRNA表达水平降低，而青年大鼠则表达升高。当前的结构数据证实，L-655,708对低浓度异氟烷麻醉所致的老年大鼠空间学习记忆损害只有预防作用，而无治疗作用。

orcid: 0000-0002-1130-6676 (Yi-Qing Yin)
           0000-0003-4939-7048 (Yong-An Wang)

关键词: 异氟烷, 术后认知功能障碍, 海马, 反向激动剂, &gamma, -氨基丁酸A型受体&alpha, 5亚单位, L-655, 708, 老年, Wistar大鼠, Morris水迷宫, 记忆功能损害, 神经再生

Abstract:

The α5 subunit-containing gamma-amino butyric acid type A receptors (α5 GABAARs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 GABAARs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose (1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young (3-month-old) and aged (24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia. The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reac¬tion showed that low-dose isoflurane decreased the mRNA expression of α5 GABAARs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China (approval No. NBCDSER-IACUC-2015128) in December 2015.

Key words: isoflurane, postoperative cognitive dysfunction, hippocampus, inverse agonist, α5 GABAA receptors, L-655,708, aged, Morris Water Maze, memory impairment, neural regeneration