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ENGLISH ABSTRACT
异氟醚通过激活PERK/eIF2α通路诱导神经元凋亡和ERS在PND中的作用机制
董营
何二涛
师荣荣
作者及单位信息
·
DOI： 10.3760/cma.j.cn321761-20211116-00603
The mechanism of isoflurane-induced neuronal apoptosis and endoplasmic reticulum stress in perioperative neurocognitive disorders via RNA-activated protein kinase-like endoplasmic reticulum kinase/eukaryotic translation initiation factor 2α pathway
Dong Ying
He Ertao
Shi Rongrong
Authors Info & Affiliations
Dong Ying
Department of Anesthesiology, Dingzhou People's Hospital, Dingzhou 073000, China
He Ertao
Department of Anesthesiology, the Second Hospital of Lanzhou University, Lanzhou 730000, China
Shi Rongrong
Department of Anesthesiology, Dingzhou People's Hospital, Dingzhou 073000, China
·
DOI： 10.3760/cma.j.cn321761-20211116-00603
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摘要

目的探究异氟醚通过激活蛋白激酶样内质网激酶（protein kinase-like endoplasmic reticulum kinase, PERK）/真核翻译起始因子2α（eukaryotic translation initiation factor 2α, eIF2α）通路诱导神经元凋亡和内质网应激（endoplasmic reticulum stress, ERS）在围手术期神经认知障碍（perioperative neurocognitive disorders, PND）中的作用机制。

方法30只雄性SD大鼠按随机数字表法分为3组（每组10只）：对照组、异氟醚组和PERK抑制剂组（GSK组）。异氟醚组和GSK组大鼠放置于麻醉箱，通过吸入2%异氟醚4 h建立PND模型，GSK组大鼠在吸入异氟醚6 h前使用PERK抑制剂GSK2606414（150 mg/kg）灌胃；对照组大鼠进行同样处理，但不吸入异氟醚，给予等量生理盐水灌胃。吸入异氟醚4 h后进行水迷宫试验，记录逃避潜伏期、穿越平台次数和目标象限停留时间，分析大鼠神经功能。水迷宫实验结束后处死大鼠取海马组织，TUNEL染色检测海马组织神经元细胞凋亡率，Western blot法检测海马组织PERK、eIF2α磷酸化水平及78 kDa葡糖调节蛋白（78 kDa glucose-regulated protein, GRP78）、C/EBP同源蛋白（C/EBP homologous protein, CHOP）水平，免疫组化染色检测海马组织B淋巴细胞瘤-2（B-cell lymphoma-2, Bcl-2）、B淋巴细胞瘤-2-Associated X（B-cell lymphoma-2-Associated X, Bax）水平。

结果异氟醚组逃避潜伏期长于GSK组及对照组（ P<0.05），穿越平台次数和目标象限停留时间少于GSK组及对照组（ P<0.05）。异氟醚组海马组织神经元细胞凋亡率高于GSK组及对照组（ P<0.05），PERK、eIF2α磷酸化水平高于GSK组及对照组（ P<0.05），GRP78、CHOP水平高于GSK组及对照组（ P<0.05），Bax水平高于GSK组及对照组，Bcl-2水平低于GSK组及对照组（ P<0.05）。

结论异氟醚可能通过激活PERK/eIF2α通路和ERS引起海马组织神经元细胞凋亡，抑制PERK/eIF2α通路的激活可通过抑制ERS缓解海马组织神经元细胞凋亡从而对PND模型大鼠的神经功能起到保护作用。

麻醉;异氟醚;围手术期神经认知障碍;海马;内质网应激;凋亡
ABSTRACT

ObjectiveTo explore the mechanism of isoflurane-induced neuronal apoptosis and endoplasmic reticulum stress (ERS) through protein kinase-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2α (eIF2α) pathway in perioperative neurocognitive disorders (PND).

MethodsThirty male Sprague-Dawley (SD) rats were divided into three groups by random number table method with ten rats in each group: the control group, isoflurane group, and PERK inhibitor group (GSK group). Rats in the isoflurane group and GSK group were placed in an anesthesia box, and the PND model was established by inhaling 2% isoflurane for 4 h. The rats in the GSK group were given PERK inhibitor GSK2606414 (150 mg/kg) by gavage once 6 h before inhalation of isoflurane. Rats in the control group received the same treatment, but did not inhale isoflurane, and were given the same amount of normal saline by gavage. Four hours after inhalation of isoflurane, the neurological function of the rats was tested by a water maze, the escape latency, the number of mice crossing the platform, and the residence time in the target quadrant were recorded. After the experiment, the rats were killed and their hippocampal tissue was taken. TUNEL staining was used to detect the apoptosis rate in the hippocampus. Western blot was used to detect the the phosphorylated levels of PERK and eIF2α and the levels of 78 kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP). Immunohistochemical staining was used to detect B-cell lymphoma-2-Associated X (Bax) and B-cell lymphoma-2 (Bcl-2) levels in the hippocampus.

ResultsThe escape latency in the isoflurane group was higher than that in the GSK group and the control group ( P<0.05). The crossed platform times and the target quadrant stay time in the isoflurane group were lower than those in the GSK group and the control group ( P<0.05). The phosphorylated levels of PERK and eIF2α in the hippocampus of isoflurane group were higher than those of GSK group and control group ( P<0.05). The levels of GRP78 and CHOP in the hippocampus of rats in the isoflurane group were higher than those in the GSK group and control group ( P<0.05). The apoptosis rate in the hippocampus of the rats in the isoflurane group was higher than that in the GSK group and the control group ( P<0.05). Bax in the hippocampus of the isoflurane group was higher than that of the GSK group and control group, and Bcl-2 was lower than that of the GSK group and control group ( P<0.05).

ConclusionsIsoflurane may induce apoptosis of hippocampal neurons by activating the PERK/eIF2α pathway and ERS, and inhibiting the activation of the PERK/eIF2α pathway can alleviate hippocampal neuronal apoptosis by inhibiting ERS, thereby protecting the neurological function of PND model rats.

Anesthesia;Isoflurane;Perioperative neurocognitive disorders;Hippocampus;Endoplasmic reticulum stress;Apoptosis
Dong Ying, Email: mocdef.3ab611100nibiloahz
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引用本文

董营,何二涛,师荣荣. 异氟醚通过激活PERK/eIF2α通路诱导神经元凋亡和ERS在PND中的作用机制[J]. 国际麻醉学与复苏杂志,2022,43(08)：789-794.

DOI:10.3760/cma.j.cn321761-20211116-00603

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围手术期神经认知障碍（perioperative neurocognitive disorders, PND）是患者术后的主要并发症，会导致患者神经功能受损、围手术期发病率和病死率增加，并且PND在老年患者中的发病率显著高于年轻患者 [ 1 , 2 ]。异氟醚作为吸入型麻醉剂已在临床实践和研究中得到广泛应用，最近越来越多的临床数据证明异氟醚的使用会增加PND的发生风险 [ 3 ]。目前关于PND的发病机制尚不清楚，研究认为可能与各种原因引起的氧化应激反应和炎症损伤有关，内质网应激（endoplasmic reticulum stress, ERS）是细胞对压力或损伤的早期或初始反应，并与神经退行性疾病中的神经元损伤或死亡有关，如阿尔茨海默病、帕金森病等 [ 4 , 5 ]。ERS反应会引起未折叠蛋白反应（unfolded protein response, UPR），引起蛋白激酶样内质网激酶（protein kinase-like endoplasmic reticulum kinase, PERK）和真核翻译起始因子2α（eukaryotic translation initiation factor 2α, eIF2α）的过度磷酸化，并进一步引起78 kDa葡糖调节蛋白（78 kDa glucose-regulated protein, GRP78）和C/EBP同源蛋白（C/EBP homologous protein, CHOP）水平的升高，导致细胞凋亡 [ 6 ]。研究显示，麻醉会引起内质网相关蛋白PERK和CHOP水平的升高，而抑制麻醉小鼠机体的ERS反应可缓解术后小鼠的认知功能减退，并抑制神经元细胞凋亡 [ 7 ]。一项最新的研究显示，异氟醚可通过调节ERS参与β淀粉样蛋白诱导的大鼠PC12细胞凋亡过程 [ 8 ]。以上这些研究提示异氟醚可能通过激活ERS引起海马组织神经元细胞凋亡从而导致PND。本研究主要分析ERS在PND中的作用并探讨通过PERK抑制剂GSK2606414阻断ERS对老年PND大鼠模型神经功能的影响。
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参考文献
[1]
Daiello LA , Racine AM , Yun Gou R ,et al. Postoperative delirium and postoperative cognitive dysfunction: overlap and divergence[J]. Anesthesiology, 2019,131(3):477-491. DOI: 10.1197/ALN.0000000000002729 .
返回引文位置Google Scholar
百度学术
万方数据
[2]
Urits I , Orhurhu V , Jones M ,et al. Current perspectives on postoperative cognitive dysfunction in the ageing population[J]. Turk J Anaesthesiol Reanim, 2019,47(6):439-447. DOI: 10.5152/TJAR.2019.75299 .
返回引文位置Google Scholar
百度学术
万方数据
[3]
Song J , Chu S , Cui Y ,et al. Circadian rhythm resynchronization improved isoflurane-induced cognitive dysfunction in aged mice[J]. Exp Neurol, 2018,306:45-54. DOI: 10.1016/j.expneurol.2018.04.009 .
返回引文位置Google Scholar
百度学术
万方数据
[4]
Wang HF , Wang ZQ , Ding Y ,et al. Endoplasmic reticulum stress regulates oxygen-glucose deprivation-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS[J]．CNS Neurosci Ther, 2018,24(1):29-38. DOI: 10.1111/cns.12771 .
返回引文位置Google Scholar
百度学术
万方数据
[5]
Liu Y , Wen D , Gao J ,et al. Methamphetamine induces GSDME-dependent cell death in hippocampal neuronal cells through the endoplasmic reticulum stress pathway[J]. Brain Res Bull, 2020,162:73-83. DOI: 10.1016/j.brainresbull.2020.06.005 .
返回引文位置Google Scholar
百度学术
万方数据
[6]
Wan H , Wang Q , Chen X ,et al. WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death[J]. Autophagy, 2020,16(3):531-547. DOI: 10.1080/15548627.2019.1630224 .
返回引文位置Google Scholar
百度学术
万方数据
[7]
Wang B , Ge S , Xiong W ,et al. Effects of resveratrol pretreatment on endoplasmic reticulum stress and cognitive function after surgery in aged mice[J/OL]. BMC Anesthesiol, 2018,18(1):141. DOI: 10.1186/s12871-018-0606-5 .
返回引文位置Google Scholar
百度学术
万方数据
[8]
邹泳国,周春燕,朴美花,等. 异氟醚对β淀粉样蛋白诱导的大鼠PC12细胞凋亡和内质网应激的影响及其机制[J]. 吉林大学学报(医学版), 2014,40(2):224-228,插1. DOI: 10.13481/j.1671-587x.20140202 .
返回引文位置Google Scholar
百度学术
万方数据
[9]
陈磊,孙玲玲,许鑫,等. 海马大麻素2型受体在小鼠术后认知功能障碍中的作用[J]. 中华麻醉学杂志, 2018,38(5):536-540. DOI: 10.3760/cma.j.issn.0254-1416.2018.05.007 .
返回引文位置Google Scholar
百度学术
万方数据
[10]
Mercado G , Castillo V , Soto P ,et al. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease[J]. Neurobiol Dis, 2018,112:136-148. DOI: 10.1016/j.nbd.2018.01.004 .
返回引文位置Google Scholar
百度学术
万方数据
[11]
Lv X , Yan J , Jiang J ,et al. MicroRNA-27a-3p suppression of peroxisome proliferator-activated receptor-γ contributes to cognitive impairments resulting from sevoflurane treatment[J]. J Neurochem, 2017,143(3):306-319. DOI: 10.1111/jnc.14208 .
返回引文位置Google Scholar
百度学术
万方数据
[12]
Cascella M , Muzio MR , Bimonte S ,et al. Postoperative delirium and postoperative cognitive dysfunction: updates in pathophysiology, potential translational approaches to clinical practice and further research perspectives[J]. Minerva Anestesiol, 2018,84(2):246-260. DOI: 10.23736/S0375-9393.17.12146-2 .
返回引文位置Google Scholar
百度学术
万方数据
[13]
Furmanik M , van Gorp R , Whitehead M ,et al. Endoplasmic reticulum stress mediates vascular smooth muscle cell calcification via increased release of grp78 (glucose-regulated protein, 78 kda)-loaded extracellular vesicles[J]. Arterioscler Thromb Vasc Biol, 2021,41(2):898-914. DOI: 10.1161/ATVBAHA.120.315506 .
返回引文位置Google Scholar
百度学术
万方数据
[14]
Bachar-Wikstrom E , Manchanda M , Bansal R ,et al. Endoplasmic reticulum stress in human chronic wound healing: Rescue by 4-phenylbutyrate[J]. Int Wound J, 2021,18(1):49-61. DOI: 10.1111/iwj.13525 .
返回引文位置Google Scholar
百度学术
万方数据
[15]
Hetz C , Saxena S . ER stress and the unfolded protein response in neurodegeneration[J]. Nat Rev Neurol, 2017,13(8):477-491．DOI: 10.1038/nrneurol.2017.99 .
返回引文位置Google Scholar
百度学术
万方数据
[16]
Yu Y , Yu R , Men W ,et al. Psoralen induces hepatic toxicity through PERK and ATF6 related ER stress pathways in HepG2 cells[J]. Toxicol Mech Methods, 2020,30(1):39-47. DOI: 10.1080/15376516.2019.1650150 .
返回引文位置Google Scholar
百度学术
万方数据
[17]
张勇,黄春来,付婷婷,等. 小檗碱对果糖诱导人肾小管细胞内质网应激PERK凋亡通路的影响[J]. 解放军医学杂志, 2017,42(1):6-11. DOI: 10.11855/j.issn.0577-7402.2017.01.02 .
返回引文位置Google Scholar
百度学术
万方数据
[18]
Xu Q , Chen C , Lin A ,et al. Endoplasmic reticulum stress-mediated membrane expression of CRT/ERp57 induces immunogenic apoptosis in drug-resistant endometrial cancer cells[J]. Oncotarget, 2017,8(35):58754-58764. DOI: 10.18632/oncotarget.17678 .
返回引文位置Google Scholar
百度学术
万方数据
[19]
Abdulkarim B , Hernangomez M , Igoillo-Esteve M ,et al. Guanabenz sensitizes pancreatic β cells to lipotoxic endoplasmic reticulum stress and apoptosis[J]. Endocrinology, 2017,158(6):1659-1670. DOI: 10.1210/en.2016-1773 .
返回引文位置Google Scholar
百度学术
万方数据
[20]
Tang J , Yu W , Chen S ,et al. Microglia polarization and endoplasmic reticulum stress in chronic social defeat stress induced depression mouse[J]. Neurochem Res, 2018,43(5):985-994．DOI: 10.1007/s11064-018-2504-0 .
返回引文位置Google Scholar
百度学术
万方数据
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董营，Email： mocdef.3ab611100nibiloahz
B

董营、何二涛、师荣荣：实验操作、论文撰写；董营、何二涛：数据整理、统计分析；董营：研究指导、论文修改、经费支持

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河北省医学科学研究重点课题计划 (20181474)
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