Zhao Zi-Fang, Du Lei, Gao Teng, Bao Lin, Luo Yuan, Yin Yi-Qing, Wang Yong-An
Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China.
Department of Radiology, China-Japan Friendship Hospital, Beijing, China.
Neural Regen Res. 2019 Jun;14(6):1029-1036. doi: 10.4103/1673-5374.250621.
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 reaction 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.
含α5亚基的A型γ-氨基丁酸受体（α5 GABAARs）是一个独特的亚群，特异性分布于哺乳动物海马体中，并且介导海马神经元的强直抑制性电流。这些强直电流可被低剂量异氟烷增强，这与学习和记忆损伤有关。α5 GABAARs的反向激动剂，如L-655,708，能够逆转低剂量异氟烷在幼龄动物中引起的短期记忆缺陷。然而，这些负变构调节剂对老年大鼠是否具有相同作用仍不清楚。在本研究中，我们主要研究了L-655,708对低剂量（1.3%）异氟烷诱导的老年大鼠学习和记忆损伤的影响。将年轻（3月龄）和老年（24月龄）Wistar大鼠随机分组，在1.3%异氟烷麻醉前0.5小时或麻醉后23.5小时给予L-655,708。莫里斯水迷宫试验表明，麻醉前或麻醉后注射L-655,708均可逆转幼龄大鼠的记忆缺陷。但在老年大鼠中，仅在麻醉前应用L-655,708显示出类似效果。逆转录-聚合酶链反应表明，低剂量异氟烷降低了老龄海马神经元中α5 GABAARs的mRNA表达，但增加了幼龄动物中的表达。这些发现表明，L-655,708可预防但不能逆转1.3%异氟烷诱导的老年Wistar大鼠空间学习和记忆损伤。所有实验程序和方案均于2015年12月获得中国军事医学科学院实验动物伦理委员会批准（批准号：NBCDSER-IACUC-2015128）。
