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   复旦学报(医学版)  2023, Vol. 50 Issue (3): 412-418      DOI: 10.3969/j.issn.1672-8467.2023.03.013
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七氟醚-N2O麻醉对青年小鼠空间学习和记忆功能及pCREB和Egr1表达的影响
王蓓 , 周国霞     
复旦大学附属肿瘤医院麻醉科-复旦大学上海医学院肿瘤学系 上海 200032
摘要目的 研究七氟醚-N2O麻醉后青年小鼠的空间学习和记忆能力以及海马磷酸化环腺苷酸应答元件结合蛋白(phosphorylated cyclic AMP response element-binding protein,pCREB)和早期生长反应因子1(early growth response factor 1,Egr1)的表达,并与老年小鼠进行比较。方法 12只3月龄和12只18月龄小鼠随机分为对照组和实验组,每组各6只。48 h后进行为期6天的获得训练。获得训练结束后24 h进行空间探索实验,实验结束后15 min收集两组小鼠的海马组织,通过Western blot和实时定量PCR方法评估pCREB和Egr1的表达水平。结果 未见麻醉损害青年小鼠的空间学习和记忆功能以及海马中pCREB和Egr1的表达水平,麻醉组与对照组比较差异均无统计学意义;而老年小鼠Sev+N2O组在麻醉后第4、5、6天逃逸潜伏期显著长于对照组(P < 0.05),两组小鼠游泳速度差异无统计学意义;在空间探索实验中,Sev+N2O组目标象限路程百分比和时间百分比显著低于对照组(P < 0.01);海马中pCREB和Egr1的表达水平均较对照组显著下降(P < 0.05)。结论 七氟醚-N2O麻醉对青年小鼠的空间学习记忆能力没有损害,也不影响海马中pCREB和Egr1的表达,但会对老年小鼠造成损害。
关键词七氟醚    一氧化二氮(N2O)    环腺苷酸应答元件结合蛋白(pCREB)    早期生长反应因子1(Egr1)    小鼠    Morris水迷宫    
Effect of sevoflurane-N2O anesthesia on spatial learning and memory function and the expression of pCREB and Egr1 in young mice
WANG Bei , ZHOU Guo-xia     
Department of Anesthesia, Fudan University Shanghai Cancer Center-Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Abstract: Objective To investigate spatial learning and memory and expression of phosphorylated cyclic AMP response element-binding protein (pCREB) and early growth response factor 1 (Egr1) in hippocampus of young mice anesthetized with Sevoflurane-nitrous oxide, compared with aged mice. Methods The mice aged 3 months (n=12) and 18 months (n=12) were randomly assigned to the experiment group and the control group, respectively, and there were 6 young mice and 6 old mice in each group. The mice in the experiment group were given 1.0 MAC sevoflurane, 70% N2O and 30% oxygen for 4 h, while mice in the control group were given 30% oxygen for 4 h. A 6-day acquisition training was conducted 48 h after exposure. The probe trial was conducted 24 h after training. Collecting hippocampal tissues 15 min after the probe trial and the expression of pCREB and Egr1 were assessed by Western blot and real-time quantitative PCR. Results There was no significant difference in spatial learning and memory as well as the expression of pCREB and Egr1 in hippocampus between the Sev+N2O group and the control group in young mice. In aged mice, the escape latency of the Sev+N2O group was significantly longer compared with the control group on day 4, 5 and 6 (P < 0.05). The difference of the swimming speed between the two groups was not significant. During the spatial probe test, the percentage of distance and time in the target quadrant of the Sev+N2O group was significantly lower than that of the control group (P < 0.01). The expression of pCREB and Egr1 in the hippocampus was significantly decreased compared with the control group (P < 0.05). Conclusion Sevoflurane-nitrous oxide anesthesia did not impair spatial learning and memory of young mice, nor did it affect the expression of pCREB and Egr1 in hippocampus, but it did impair the aged mice.
Key words: sevoflurane    nitrous oxide (N2O)    cyclic AMP response element-binding protein (pCREB)    early growth response protein 1 (Egr1)    mice    Morris water maze    

麻醉和手术会导致老年人术后长期认知能力下降,而且风险随着年龄的增长而增加,接受大手术的老年患者是发生术后认知功能障碍(post-operative cognitive dysfunction,POCD)的高危人群,术后1周发生率为25.8%,术后3个月发生率为9.9%[1]。吸入麻醉药(如七氟醚)可能的毒性作用及其对POCD的潜在影响越来越引起关注[2]

七氟醚和N2O具有诸多优点,在临床麻醉中使用广泛。研究发现,七氟醚可以诱导年轻小鼠Tau蛋白磷酸化[3],并可诱导Tau蛋白从神经元转移到小胶质细胞,IL-6生成增加,导致认知能力障碍[4]。我们研究发现[5],七氟醚/N2O麻醉使老年大鼠海马内cAMP/CREB信号通路下调、环腺苷酸应答元件结合蛋白(cyclic AMP response element-binding protein,CREB)依赖性神经发生减少和海马神经元存活率降低,最终导致空间学习习得和记忆保留的显著缺陷。关于七氟醚-N2O麻醉是否会影响青年小鼠的空间认知能力及其机制目前尚不清楚。长期记忆的形成取决于新蛋白质的合成,而CREB是参与该过程的典型介质,调节与突触可塑性相关的基因转录。磷酸化CREB((phosphorylated CREB,pCREB)水平会在记忆训练后升高,其降低会损害空间记忆[6-7]。早期生长反应因子1(early growth response factor 1,Egr1)是一种即刻早期基因(immediate early genes,IEGs),又称为zif268、krox-24、NGFI-A或者ZENK,是CREB下游基因并受其调控[8]。在缺乏IEGs的小鼠中,海马体中的突触可塑性被破坏,zif268敲除小鼠的齿状回中的晚期长时程增强(long term potentiation,LTP)受损,在这些动物中也观察到相应的学习缺陷[9]。本研究旨在观察未手术的情况下七氟醚-N2O麻醉4 h是否会影响青年小鼠空间学习记忆功能以及海马pCREB和Egr1表达,并与老年小鼠进行比较。

材料和方法

动物模型  3月龄[体质量(30±1.5)g]和18月龄[体质量(40±1.5)g]清洁级雄性C57/BL6小鼠购自上海斯莱克实验动物有限责任公司,标准实验条件下饲养,即自由进食、饮水,12 h明暗交替的光照周期。所有实验都在有光照的周期(7∶00—17∶00)内进行。实验经复旦大学附属肿瘤医院实验动物管理和使用委员会批准(批准号:FUSCC-IACUC-S20210245)。将12只老年小鼠和12只青年小鼠分别随机分为麻醉组(给予1.0 MAC七氟醚、70% N2O、30%氧气,吸入4 h)和对照组(给予30%氧气,吸入4 h),每组各6只。新鲜气流经过预先湿化,再进入麻醉箱,流量为2 L/min,麻醉过程中持续监测七氟醚、N2O浓度和呼气末二氧化碳分压。在麻醉箱下放置电热毯维持小鼠体温,温度设置为38 ℃。麻醉结束后,让小鼠恢复自主呼吸,待清醒后放回笼中。48 h后进行为期6天的水迷宫训练。每只小鼠每天进行4次实验(间隔15 min),每一次实验在其中一个象限(按随机顺序)将小鼠放入水池,并让它进入水下平台。在每次实验中,小鼠被允许游泳最多60 s,到达平台之前所花的时间(即逃逸潜伏期)是空间获得训练的衡量指标。如果小鼠在60 s内找不到平台,则将其引导到平台上,逃逸潜伏期记录为60 s,小鼠被允许在平台上停留15 s。然后从池中移出,用毛巾擦干,回到热灯下的笼子中,以恢复核心温度。每次实验释放点不同,每天使用不同的释放点顺序。获得训练结束24 h后,小鼠进行探索实验,移除平台,从平台所在目标象限对面的象限开始,每只小鼠游泳60 s,评估记忆保留时长。

Western blot  探索实验结束后15 min处死小鼠,快速取出脑组织,分离海马组织。将取得的脑组织加入免疫沉淀反应缓冲液[含10 mmol/L Tris-HCl(pH=7.4)、150 mmol/L NaCl、2 mmol/L EDTA、0.5% Nonidet P-40为主要成分]和蛋白酶抑制剂(含1 μg/mL抑肽酶、1 μg/mL亮抑肽酶和1 μg/mL胃酶抑素A),研磨彻底,12 000 rpm(离心半径6.2 cm)离心提取蛋白裂解液上清,将蛋白样品30 μg加入SDS-PAGE(10%凝胶剂)电泳分离,湿法转膜(PVDF膜)。室温下用5%胎牛血清封闭1 h,4 ℃下与以下一抗杂交过夜:Egr1(44D5)、p-CREB(美国CST公司)或β-actin(美国Santa Cruz公司)。第2天与二抗室温孵育1 h后显影。

RT-PCR检测  研碎海马组织,总RNA用Trizol试剂盒(美国Invitrogen公司)提取,具体步骤按照说明书。采用SYBR Green RT-PCR检测cDNA的量,以GAPDH作为内参,平衡不同样本之间组织量的差异。定量PCR引物如表 1所示,反应体系为25 μL,两步法反应程序:95 ℃ 2 min,95 ℃ 15 s,58 ℃ 20 s,72 ℃ 20 s,40个循环后接溶解曲线反应。每次实验每个反应做3个平行重复孔,实验独立重复3次。

表 1 引物序列 Tab 1 Primer sequence
Gene Sequence
CREB Forward:5’-TCCAGGTCCATGGCGTTAT-3’
Reverse:5’-TCTTCAATCCTTGGCACCC-3’
Egr1 Forward:5’-TCCCAGCTCATCAAACCCA-3’
Reverse:5’-GGCAAACTTCCTCCCACAAA-3’
GAPDH Forward:5’-GCCTTCCGTGTTCCTACC-3’
Reverse:5’-AGAGTGGGAGTTGCTGTTG-3’

统计学方法  使用Image J软件分析Western blot条带的灰度值。所有数据均用x±s表示。应用SPSS 17.0软件进行统计分析。逃逸潜伏期和游泳速度比较采用重复测量双因素方差分析,不同时间点各组差异的比较采用Bonferroni法进行两两比较分析。空间探索实验中平台象限时间、路程百分比,条带的相对灰度值及RT-PCR数据的比较采用单因素方差分析。P < 0.05为差异有统计学意义。

结果

水迷宫行为学结果  青年小鼠中,Sev+N2O组逃逸潜伏期(F=1.22,P=0.274 7)、游泳速度(F=0.67,P=0.418 6)、平台象限路程百分比(F=2.35,P=0.135 8)和时间百分比(F=1.8,P=0.190 0)与对照组比较,差异均无统计学意义;Sev+N2O组和对照组平台象限路程百分比显著高于其他3个象限(Sev+N2O组:E vs. S,F=8.90 P=0.005 7;E vs. N,F=18.2,P=0.000 2;E vs. W,F=28.07,P < 0.000 1;对照组:E vs. S,F=8.22,P=0.0062;E vs. N,F=14.59,P=0.000 4;E vs. W,F=29.79,P < 0.000 1)(图 1)。老年小鼠水迷宫中学习的空间获取如图 2A所示,描述了到达平台的逃逸潜伏期。对照组和Sev+N2O组在习得阶段表现出空间学习和记忆的改善,但后者达到目标象限的潜伏期更长。Sev+N2O组在麻醉第4天(F=5.28,P=0.029 0)、第5天(F=5.34,P=0.028 1)和第6天(F=4.96,P=0.030 8)分别出现了学习障碍(图 2A)。两组小鼠游泳速度差异无统计学意义(F=0.70,P=0.409 8)(图 2B)。在空间探索实验中,Sev+N2O组目标象限路程百分比(F=11.05,P=0.001 7)和时间百分比(F=8.22,P=0.006 2)显著低于对照组(图 2C2E);Sev+N2O组平台象限路程百分比显著高于相对象限(F=12.35,P < 0.000 1),而与相邻象限差异无统计学意义(E vs. S:F=2.15,P=0.149 2;E vs. N:F=0.49,P=0.490 4)(图 2D)。

A: Mean escape latency to find the hidden platform across training days; B: Swimming speed during training days; C: Percentage of distance traveled in the target quadrant; D: Percentage of distance traveled in each quadrant; E: Percentage of time spent in the target quadrant.(1)vs. target quadrant, P < 0.01. 图 1 青年小鼠在水迷宫中学习和记忆的结果 Fig 1 Spatial learning and memory tested by the Morris water maze in young mice
A: Mean escape latency to find the hidden platform across training days; B: Swimming speed during training days; C: Percentage of distance traveled in the target quadrant; D: Percentage of distance traveled in each quadrant; E: Percentage of time spent in the target quadrant. (1)vs. control group, P < 0.05; (2)vs. target quadrant, P < 0.001. 图 2 老年小鼠在水迷宫中学习和记忆的结果 Fig 2 Spatial learning and memory tested by the Morris water maze in aged mice

海马pCREB和Egr1蛋白的表达  老年小鼠Sev+N2O组海马pCREB和Egr1蛋白表达较对照组显著下降(F=32.968,P=0.005;F=7.978,P=0.048),而青年小鼠两组之间海马pCREB和Egr1蛋白表达差异无统计学意义(F=0.478,P=0.540;F=0.873,P=0.421)(图 3)。

A: Western blot images of Egr1 and β-actin in aged mice; B: Western blot images of pCREB and β-actin in aged mice; C: Quantification of Egr1 and pCREB in aged mice(n=3 for each group); D: Western blot images of Egr1 and β-actin in young mice; E: Western blot images of pCREB and β-actin in young mice; F: Quantification of Egr1 and pCREB in young mice (n=3 for each group).(1)vs. control group, P < 0.05. 图 3 老年小鼠和青年小鼠海马Egr1和pCREB蛋白表达 Fig 3 Expressions of Egr1 and pCREB in hippocampus of aged and young mice

海马CREB和Egr1 mRNA的表达  老年小鼠Sev+N2O组海马Egr1 mRNA表达显著低于对照组(F=6.437,P=0.034)(图 4A);青年小鼠Sev+N2O组海马Egr1 mRNA表达与对照组比较差异无统计学意义(F=1.267,P=0.296)(图 4C);老年小鼠和青年小鼠海马CREB mRNA表达Sev+N2O组与对照组比较差异无统计学意义(F=1.241,P=0.298;F=1.135,P=0.310)(图 4B4D)。

A: Expression of Egr1 mRNA in aged mice; B: Expression of CREB mRNA in aged mice; C: Expression of Egr1 mRNA in young mice; D: Expression of CREB mRNA in young mice. (1)vs. control group, P < 0.05. 图 4 老年和青年小鼠海马CREB和Egr1mRNA的表达 Fig 4 Expressions of CREB mRNA and Egr1 mRNA in hippocampus of aged and young mice
讨论

七氟醚是当前临床常用吸入麻醉药,N2O是经典合用吸入麻醉气体,两者具有诱导快,吸收和清除迅速,对循环抑制轻等优点。本文主要研究七氟醚-N2O全身麻醉对青年小鼠的空间认知功能和生化的影响,并与老年小鼠进行对照。我们发现,3月龄小鼠在不接受手术的情况下暴露于1.0 MAC七氟醚和70% N2O 4 h后没有出现认知功能障碍,而18月龄小鼠的空间学习记忆能力受到了损害。我们推测这种损伤不是由麻醉药物残留引起的,因为七氟醚的时量相关半衰期小于5 min,90%递减时间在麻醉6 h后为65 min[10],N2O的血气分配系数比七氟醚更小,苏醒更迅速,90%递减时间更短,而直到麻醉结束48 h后才进行水迷宫训练。有研究表明七氟醚麻醉4 h对青年和老年大鼠的获得性学习和保留记忆无损害[11];也有研究表明七氟醚可以诱导年轻小鼠Tau蛋白磷酸化和认知障碍[3]。异氟醚和七氟醚通过激活小胶质细胞,产生神经炎症,并抑制VEGFR2信号通路来抑制神经干细胞的发育和神经生成,导致出生后7天的大鼠认知功能损害[12]。Culley等[13]研究表明,接受异氟醚和N2O麻醉的老年大鼠在全身麻醉后至少2周的空间记忆任务表现较差,诱发的损伤可能比单独使用异氟醚更严重。据报道,老年大鼠仅接触N2O 4 h可导致长达2周的学习障碍[14]。最近的研究表明,七氟醚,而不是地氟醚,增加了血液、神经元培养液或细胞外囊泡中的Tau或p-Tu数量;增加了脑间质液中p-tau蛋白的含量,Tau蛋白可以通过磷酸化从神经元转运到小胶质细胞,激活NF-kB信号通路,产生促炎细胞因子IL-6,导致认知损害[4]。研究发现,七氟醚麻醉对老年大鼠记忆功能有明显影响,并诱导海马神经元凋亡[15-17]。3%七氟醚持续吸入8 h后,老年大鼠在麻醉后第1天和第3天出现认知功能下降,海马区RGS2表达下调[18]。我们研究发现[19],七氟醚麻醉下调海马Egr1表达和CREB磷酸化水平,影响老年小鼠空间认知能力。尽管吸入麻醉-POCD模型已被充分证明,但仍存在争议。不同的方法(包括不同的麻醉、剂量、大小鼠品系、暴露时间、结果测量和麻醉载体气体),可能导致了这些矛盾的结果。我们使用1.0 MAC的七氟醚和70% N2O作为麻醉剂,30%氧气作为载体气体,这可能是造成差异的因素之一。POCD的确切分子生物学机制目前尚不清楚。如前所述,pCREB是参与长时记忆形成的典型介质,记忆训练后pCREB水平升高,其降低会损害空间记忆。Egr1敲除小鼠的齿状回中的LTP受损并观察到相应的学习缺陷[9]。本研究中,我们测量了空间探索实验结束后15 min海马中pCREB和Egr1的水平。结果发现,青年小鼠Sev+N2O组的pCREB和Egr1水平与对照组之间差异无统计学意义,而老年小鼠Sev+N2O组显著低于对照组。本研究结果表明,七氟醚-N2O麻醉不影响青年小鼠pCREB和Egr1水平,但降低了老年小鼠pCREB和Egr1水平,并至少持续到空间探索实验结束,这将影响pCREB和Egr1维持LTP和长期记忆的能力。Egr1是CREB下游记忆相关基因,并受CREB的调控,在海马神经元中超过生理水平的Gadd45γ可以破坏记忆形成所需的CREB磷酸化和依赖CREB的记忆相关基因(包括Egr1)表达,导致空间识别记忆损害[20]。丘脑外侧背核CREB下调可恶化大鼠在Morris水迷宫行为训练后的记忆巩固[21]zif268基因敲除小鼠的长期记忆受损,但短期记忆保持完好,包括空间学习[22]。以上都支持本研究结果,即麻醉组青年小鼠的学习和记忆与对照组相比差异无统计学意义,两组小鼠海马内Egr1和CREB磷酸化水平的差异也无统计学意义,而老年小鼠认知功能、海马pCREB和Egr1的表达均下降。这可能与老年小鼠的脑组织对麻醉药物更加敏感有关,具体机制需要进一步研究。

本研究存在一定的局限性:首先,未行手术,结果可能不足以促进临床研究;其次,只做了一次4 h麻醉,不能说明多次麻醉或更长时间的麻醉对老年小鼠和青年小鼠空间学习和记忆能力的影响;另外,未对记忆的保留进行长时间观察,不能说明七氟醚麻醉对认知功能的长期影响。

综上所述,本研究显示七氟醚-N2O麻醉未损害青年小鼠的获得性学习和记忆保留,也未影响其海马pCREB和Egr1的表达,但是对老年小鼠造成了损害,可能与老年脑更加脆弱有关,确切机制有待进一步研究。

作者贡献声明  王蓓  数据采集、统计和分析,论文撰写和修订。周国霞  论文撰写和修订,研究设计和指导。

利益冲突声明  所有作者均声明不存在利益冲突。

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文章信息

王蓓, 周国霞
WANG Bei, ZHOU Guo-xia
七氟醚-N2O麻醉对青年小鼠空间学习和记忆功能及pCREB和Egr1表达的影响
Effect of sevoflurane-N2O anesthesia on spatial learning and memory function and the expression of pCREB and Egr1 in young mice
复旦学报医学版, 2023, 50(3): 412-418.
Fudan University Journal of Medical Sciences, 2023, 50(3): 412-418.
Corresponding author
ZHOU Guo-xia, E-mail: zgx6742997@163.com.

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