异氟烷对神经认知功能的影响及其可能机制

神经药理学报 ›› 2015, Vol. 5 ›› Issue (5): 34-39.

异氟烷对神经认知功能的影响及其可能机制

吴倍，王新生，杨跃平，滕金亮

1.河北北方学院，075000，张家口，中国
2.河北北方学院附属第一医院，075000，张家口，中国

出版日期:2015-10-26 发布日期:2016-03-03
通讯作者: 滕金亮，男，教授，主任医师，硕士生导师；研究方向：临床麻醉，疼痛诊疗；E-mail：tengjinliang@126.com
作者简介:吴倍，女，硕士研究生；研究方向：吸入麻醉药与术后认知障碍；E-mail：15233412230@163.com
基金资助:
河北北方学院自然科学研究计划项目（No.120176），2016 年政府资助省级临床医学优秀人才项目

Eff ects of Isofl urane On Neurocognitive Function and Its Possible Mechanism

WU Bei, WANG Xin-sheng, YANG Yue-ping,TENG Jin-liang

1. Hebei North University ，Zhangjiakou，075000，China
2. The First Affiliated Hospital of Hebei North University，Zhangjiakou，075000，China

Online:2015-10-26 Published:2016-03-03
Contact: 滕金亮，男，教授，主任医师，硕士生导师；研究方向：临床麻醉，疼痛诊疗；E-mail：tengjinliang@126.com
About author:吴倍，女，硕士研究生；研究方向：吸入麻醉药与术后认知障碍；E-mail：15233412230@163.com
Supported by:
河北北方学院自然科学研究计划项目（No.120176），2016 年政府资助省级临床医学优秀人才项目

摘要/Abstract

摘要： 大量实验证据表明异氟烷能够引起学习和认知能力改变。这可能是其抑制N-甲基-D-天冬氨酸受体（N-methyl-D-aspartic acid receptor，NMDA）、激活γ氨基丁酸（γ-amino butyric acid，GABA）受体引起神经细胞去极化、Ca2+内流，促使激活caspase-3，造成神经元毒性。异氟烷也能够改变突触的形成及树突棘的密度，引起发育期的神经元死亡，来造成行为学改变。它过度激活钙调蛋白，抑制海马区突触长时程电位( long term potentiaton，LTP)，抑制短期记忆向长期记忆的转换。异氟烷引起蛋白激酶R样内质网激酶（PRKR-like endoplasmic reticulum kinase，PERK）磷酸化,通过一系列分子机制，诱导转录因子C/EBP同源蛋白（C/EBP homologous protein，CHOP）的表达，CHOP上调促凋亡蛋白和下调抗凋亡蛋白来促进神经元凋亡。此外，异氟烷诱导tau蛋白的高度磷酸化，形成神经纤维结，神经纤维结的形成被认为是神经失能性疾病比如阿尔茨海默病的共同病理途径。该文重点就异氟烷对神经认知的影响及其机制进行综述。

关键词: 异氟烷, 术后认知障碍, 内质网应激, 钙调蛋白

Abstract: A lot of experimental evidences showed that isoflurane can cause the change of learning and cognitive ability，resulting from the inhibition of N-methyl-D-aspartic acid（ NMDA） receptor，depolarization induced by activation of gamma aminobutyric acid（ GABA） receptor，Ca2+ influx and promote activation of caspase-3 which leads to neuronal toxicity. Volatile anesthetics could interfere with physiologic patterns of synaptogenesis and impair density of endritic spines of neurons in the developing cerebral cortex，thus causing changes in behavior. Isoflurane excessively activates calmodulin，inhibits hippocampal synaptic long term potential（ LTP） and curbs short-term memory into long-term memory conversion. Isoflurane induces PERK phosphorylation and increases the expression of CHOP by a series of molecular mechanisms. CHOP up-regulates pro-apoptotic proteins and downregulates anti-apoptotic proteins to promote neuronal apoptosis. Tau protein is highly phosphorylated in the form of nerve fibers and the formation of nerve fibers is considered as a common pathological pathway in the pathogenesis of Alzheimer’s disease. In this review，the mechanism of the general anesthetics inducing consciousness loss and its effect of central nervous system were summarized.

Key words: isoflurane, postoperative cognitive dysfunction, endoplasmic reticulum stress, calcineurin

吴倍，王新生，杨跃平，滕金亮. 异氟烷对神经认知功能的影响及其可能机制[J]. 神经药理学报, 2015, 5(5): 34-39.

WU Bei, WANG Xin-sheng, YANG Yue-ping,TENG Jin-liang. Eff ects of Isofl urane On Neurocognitive Function and Its Possible Mechanism[J]. Acta Neuropharmacologica, 2015, 5(5): 34-39.

参考文献

[1] Gerhard Rammes, Laura K Starker, Rainer Haseneder, et al. Isoflurane anaesthesia reversibly improves cognitive function and longterm potentiation (LTP) via an up-regulation in NMDA receptor 2B subunit expression[J]. Neuropharmacology, 2009, 56(3): 626–636.

[2] Su D, Zhao Y, Wang B, et al. Repeated but not single isoflurane exposure improved the spatial memory of young adult mice[J]. Acta Anaesthesiol Scand, 2011, 55: 468–473.

[3] Zhang Yi-ying, Xu Z, Wang H, et al. Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory[J]. Ann Neurol, 2012, 71(5): 687–698.

[4] Nils Schallner, Felix Ulbrich, Helen Engelstaedter H, et al. Isoflurane but not sevoflurane or desflurane aggravates injury to neurons in vitro and in vivo via p75NTR-NF-?B activation[J].Anesth Analg, 2014, 119(6): 1429-1441.

[5] Liu Jian-hui, Wang Pei-jun, Zhang Xiao-qing, et al. Effects of different concentration and duration time of isoflurane on acute and long-term neurocognitve function of young adult C57BL/6 mouse[J]. J Clin Exp Pathol, 2014, 7(9): 5828–5836.

[6] Eger EI, Liao M, Laster MJ, et al. Contrasting roles of the N-methyl-D-aspartate receptor in the production of immobilization by conventional and aromatic anesthetics[J]. Anesth Analg, 2006, 102(5): 1397–1406.

[7] Ken Solt, Jonas S Johansson, Douglas E Raines. Kinetics of anesthetic-induced conformational transitions in a four-alpha-helix bundle protein[J]. Biochemistry, 2006, 45(5): 1435–1441.

[8] Morgado-Bernal I. Learning and memory consolidation: linking molecular and behavioral data[J]. Neuroscience, 2011, 176:12–9.

[9] Laura Texidó, Mireia Martín-Satué, Elena Alberdi, et al. Amyloid β peptide oligomers directly activate NMDA receptors[J]. Cell Calcium, 2011(3), 49:184–190.

[10] Maria Talantova, Sara Sanz-Blasco, Zhang Xiao-fei, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss[J]. Proc Natl Acad Sci USA, 2013, 110: E2518–E2527.

[11] Zhen Ming, Benjamin L Griffith, George R Breese, et al. Changes in the effect of isoflurane on N-methyl-D-aspartic acid-gated currents in cultured cerebral cortical neurons with time in culture: evidence for subunit specificity[J]. Anesthesiology, 2002, 97(4): 856–867.

[12] Daniel A Clayton, Michael H Mesches, Enrique Alvarez, et al. A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the fischer 344 rat[J]. J Neurosci, 2002, 22: 3628–3637.

[13] Krapivinsky G, Krapivinsky L, Manasian Y, et al. The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1[J]. Neuron, 2003, 40(4): 775–784.

[14] Chitoshi Takayama, Inoue Y. GABAergic signaling in the developing cerebellum[J]. Anat Sci Int , 2004, 79:124–136.

[15] Zhang Guo-hua, Dong Yuan-lin, Zhang Bin, et al. Isoflurane-induced caspase-3activation is dependent on cytosolic calcium and can be attenuated by memantine[J]. J Neurosci, 2008, 28(17):4551–4560.

[16] Zhao Y L, Xiang Q, Shi Q Y, et al. GABAergic excitotoxicity injury of the immature hippocampal pyramidal neurons' exposure to isoflurane[J].Anesth Analg, 2011, 113(5):1152-1160.

[17] Fernandes C, Hoyle E, Emma Dempster, et al. Performance deficit of alpha7 nicotinic receptor knock out mice in a delayed matching-to- place task suggests a mild impairment of working/episodic-like memory[J]. Genes Brain Behav, 2006, 5(6): 433-440

[18] Ana Pocivavsek, Laura Icenogle, Edward D Levin. Ventral hippocampal alpha 7 and alpha4beta2 nicotinic receptor blockade and clozapine effects on memory in female rats[J]. Psychopharmacology, 2006, 188 (4): 597-604.

[19] Johnatan Ceccom, Emilie Bouhsira, Helene Halley, et al. Differential needs of zinc in the CA3 area of dorsal hippocampus for consolidation of contextual fear and spatial memories[J]. Learn Mem, 2013, 20: 348–351.

[20] Arthur Jochems, Motoharu Yoshida. Persistent firing supported by an intrinsic cellular mechanism in hippocampal CA3 pyramidal cells[J]. Eur J Neurosci, 2013, 38(2): 2250–2259.

[21] Katherine R Gentry, Louise M Steele, Margaret M Sedensky, et al. Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans[J]. Anesth Analg, 2013, 116(1): 185–189.

[22] Bradley H Lee, John Thomas Chan, Obhi Hazarika, et al. Early exposure to volatile anesthetics impairs long-term associative learning and recognition memory[J].PLoS One, 2014, 9(8): e105340.

[23] Rosamund F Langston, Emma R Wood. Associative recognition and the hippocampus: differential effects of hippocampal lesions on object-place, object-context and object-place-context memory[J]. Hippocampus, 2010, 20(10): 1139–1153.

[24] John P Aggleton, Julie R Dumont, Elizabeth Clea Warburton. Unraveling the contributions of the diencephalon to recognition memory: a review[J]. Learn Mem, 2011, 18(6): 384–400.

[25] Adrian Briner, Mathias De Roo, Alexandre Dayer, et al. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis[J]. Anesthesiology, 2010, 112: 546–556.

[26] Nimish K Acharya, Eric L Goldwaser, Martin M Forsberg, et al. Sevoflurane and isoflurane induce structural changes in brain vascular endothelial cells and increase blood-brain barrier permeability: Possible link to postoperative delirium and cognitive decline[J]. Brainres, 2015, 1620: 29-41.

[27] Cao Yi-yun, Ni Cheng, Li Zheng-qian, et al. Isoflurane anesthesia results in reversible ultrastructure and occludin tight junction protein expression changes in hippocampal blood-brain barrier in aged rats[J]. Neurosci Lett, 2015, 587: 51-56.

[28] Cheng Ying, He Linda, Prasad Vidhya, et al. Anesthesia-induced neuronal apoptosis in the developing retina: a window of opportunity[J].Anesth Analg, 2015, 121(5): 1325-1335.

[29] Aryaman Shalizi, Brice Gaudillière, Yuan Zeng-qiang, et al. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation[J].Science, 2006, 311(5763): 1012–1017.

[30] Isabella A. Graef, Fan Wang, Frederic Charron, et al. Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons[J]. Cell, 2003, 113(5): 657–670.

[31] Rachel D Groth, Paul G Mermelstein. Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression[J]. J Neurosci, 2003, 23(32): 8125–8134.

[32] Hafiz Mohmmad Abdul, Jennifer L Furman, Michelle A Sama, et al. Norris NFATs and Alzheimer's disease[J]. Cell Pharmacol, 2010, 2(1): 7–14.

[33] Christopher M Norris, Inga Kadish, Eric M Blalock, et al. Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer's models[J]. J. Neurosci, 2005, 25(18): 4649–4658.

[34] Hui Yang, Ge Liang, Brian Hawkings, et al. Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies[J].Anesthesiology, 2008, 109(2): 243–250.

[35] Zhang Yi-ying, Dong Yuan-lin, Wu Xu, et al. The mitochondrial pathway of anesthetic isoflurane-induced apoptosis[J]. J Biological Chemistry, 2010, 285(6):4025–4037.

[36] Isabelle M Mansuy, Mark Mayford, Betsy Jacob, et al. Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory[J]. Cell, 1998, 92(1): 39–49.

[37] Cheng Ni, Zhengqian Li, Min Qian, et al. Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling[J].Biochem Biophys Res Commun, 2015, 460(4):889-95.

[38] Karen M Doyle, Donna Kennedy, Adrienne M Gorman, et al. Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders[J].J Cellular Molecular Medicine, 2011, 15(10): 2025-2039.

[39] David Ron, Peter Walter. Signal integration in the endoplasmic reticulum unfolded protein response[J].Nat Rev Mol Cell Biol, 2007, 8(7):519-529.

[40] Hong-Wei Gea, Wen-Wen Hub, Lei-Lei Mac, et al. Endoplasmic reticulum stress pathway mediates isoflurane-induced neuroapoptosis and cognitive impairments in aged rats[J].Physiology & Behavior, 2015, 151: 16–23.

[41] Helene Le Freche, Jonathan Brouillette, Francisco-Jose Fernandez-Gomez, et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment[J]. Anesthesiology, 2012, 116: 779–787.

[42] Li Chang-sheng, Liu Su-fang, Xing Ying, et al. The Role of hippocampal tau protein phosphorylation in isoflurane-induced cognitive dysfunction in transgenic APP695 mice[J].Anesth Analg, 2014, 119(2): 413–419.

[43] Dong Yuan-lin, Wu Xu, Xu Zhi-peng, et al. Anesthetic isoflurane increases phosphorylated tau levels mediated by caspase activation and Aβ generation[J]. PLoS One, 2012, 7: e39386.

[44] Grundke-Iqbal I, Iqbal K, Tung YC, et al. Abnormal phosphorylation of the microtubuleassociated protein tau (tau) in Alzheimer cytoskeletal pathology[J]. Proc Natl Acad Sci USA, 1986, 83(13): 4913–4917.

[45] Lester I Binder, Angela L Guillozet-Bongaarts, Francisco Garcia-Sierra, et al. Tau, tangles, and Alzheimer’s disease[J].Biochim Biophys Acta, 2005, 1739:216–223.