Li Xu, Lu Fen, Li Wei, Xu Jun, Sun Xiao-Jing, Qin Ling-Zhi, Zhang Qian-Lin, Yao Yong, Yu Qing-Kai, Liang Xin-Liang
Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Cancer Hospital, Zhengzhou, Henan 450008, China.
Chin Med J (Engl). 2016 Jan 5;129(1):48-53. doi: 10.4103/0366-6999.172570.
Etomidate (R-1-[1-ethylphenyl] imidazole-5-ethyl ester) is a widely used anesthetic drug that had been reported to contribute to cognitive deficits after general surgery. However, its underlying mechanisms have not been fully elucidated. In this study, we aimed to explore the neurobiological mechanisms of cognitive impairments that caused by etomidate.
A total of 30 Sprague-Dawley rats were used and divided into two groups randomly to receive a single injection of etomidate or vehicle. Then, the rats' spatial memory ability and neuronal survival were evaluated using the Morris water maze test and Nissl staining, respectively. Furthermore, we analyzed levels of oxidative stress, as well as cyclic adenosine 3',5'-monophosphate response element-binding (CREB) protein phosphorylation and immediate early gene (IEG, including Arc, c-fos, and Egr1) expression levels using Western blot analysis.
Compared with vehicle-treated rats, the etomidate-treated rats displayed impaired spatial learning (day 4: 27.26 ± 5.33 s vs. 35.52 ± 3.88 s, t = 2.988, P = 0.0068; day 5: 15.84 ± 4.02 s vs. 30.67 ± 4.23 s, t = 3.013, P = 0.0057; day 6: 9.47 ± 2.35 s vs. 25.66 ± 4.16 s, t = 3.567, P = 0.0036) and memory ability (crossing times: 4.40 ± 1.18 vs. 2.06 ± 0.80, t = 2.896, P = 0.0072; duration: 34.00 ± 4.24 s vs. 18.07 ± 4.79 s, t = 3.023, P = 0.0053; total swimming distance: 40.73 ± 3.45 cm vs. 27.40 ± 6.56 cm, t = 2.798, P = 0.0086) but no neuronal death. Furthermore, etomidate did not cause oxidative stress or deficits in CREB phosphorylation. The levels of multiple IEGs (Arc: vehicle treated rats 100%, etomidate treated rats 86%, t = 2.876, P = 0.0086; c-fos: Vehicle treated rats 100%, etomidate treated rats 72%, t = 2.996, P = 0.0076; Egr1: Vehicle treated rats 100%, etomidate treated rats 58%, t = 3.011, P = 0.0057) were significantly reduced in hippocampi of etomidate-treated rats.
Our data suggested that etomidate might induce memory impairment in rats via inhibition of IEG expression.
依托咪酯（R-1-[1-乙基苯基]咪唑-5-乙酯）是一种广泛使用的麻醉药物，据报道可导致全身麻醉术后出现认知功能障碍。然而，其潜在机制尚未完全阐明。在本研究中，我们旨在探讨依托咪酯所致认知功能障碍的神经生物学机制。
总共使用30只Sprague-Dawley大鼠，随机分为两组，分别接受单次注射依托咪酯或赋形剂。然后，分别使用Morris水迷宫试验和尼氏染色评估大鼠的空间记忆能力和神经元存活情况。此外，我们使用蛋白质免疫印迹分析来检测氧化应激水平、环磷腺苷效应元件结合蛋白（CREB）的磷酸化水平以及即刻早期基因（IEG，包括Arc、c-fos和Egr1）的表达水平。
与接受赋形剂处理的大鼠相比，接受依托咪酯处理的大鼠表现出空间学习能力受损（第4天：27.26±5.33秒对35.52±3.88秒，t = 2.988，P = 0.0068；第5天：15.84±4.02秒对30.67±4.23秒，t = 3.013，P = 0.0057；第6天：9.47±2.35秒对25.66±4.16秒，t = 3.567，P = 0.0036）和记忆能力受损（穿越次数：4.40±1.18对2.06±0.80，t = 2.896，P = 0.0072；持续时间：34.00±4.24秒对18.07±4.79秒，t = 3.023，P = 0.0053；总游泳距离：40.73±3.45厘米对27.40±6.56厘米，t = 2.798，P = 0.0086），但未出现神经元死亡。此外，依托咪酯未引起氧化应激或CREB磷酸化缺陷。在接受依托咪酯处理的大鼠海马中，多种IEG的水平（Arc：接受赋形剂处理的大鼠为100%，接受依托咪酯处理的大鼠为86%，t = 2.876，P = 0.0086；c-fos：接受赋形剂处理的大鼠为100%，接受依托咪酯处理的大鼠为72%，t = 2.996，P = 0.0076；Egr1：接受赋形剂处理的大鼠为100%，接受依托咪酯处理的大鼠为58%，t = 3.011，P = 0.0057）显著降低。
我们的数据表明，依托咪酯可能通过抑制IEG表达诱导大鼠记忆障碍。
