围术期全麻药七氟烷对新生大鼠远期记忆损害和神经细胞焦亡的影响

doi:10.3969/j.issn.1009-976X.2023.01.013

摘要/Abstract

摘要： 目的研究围术期吸入性全麻药七氟烷对新生大鼠海马神经细胞焦亡和认知功能的影响。方法出生后7 d的SD大鼠随机分为对照组和实验组,同一环境下实验组暴露于2.8%七氟烷4 h,对照组暴露于空气中4 h,6 h后提取海马组织,western blot检测焦亡相关蛋白NLPR3、GSDMD、GSDMD-N、IL-18、IL-1β的表达变化（n=6）。另一批动物七氟烷或空气暴露处理后,与母鼠同窝继续饲养,30 d行旷场实验,33~34 d行条件恐惧性实验（n=10）。结果与对照组相比,七氟烷组幼鼠海马组织焦亡相关蛋白NLPR3、GSDMD、GSDMD-N、IL-18、IL-1β表达显著上调（P<0.001）。七氟烷组动物在条件恐惧性实验中僵直时间比对照组明显缩短（P<0.001）,旷场实验中总运动距离和中心区域时间七氟烷组与对照组差别无统计学意义（P>0.05）。结论七氟烷暴露可以导致新生大鼠记忆能力障碍,其机制可能与诱导神经细胞焦亡有关。

关键词: 七氟烷, 神经炎症, 焦亡, 认知功能

Abstract: Objective This paper investigates the effects of anesthetic sevoflurane on pyroptosis and cognitive function in the hippocampus of neonatal rats. Methods Sprague-Dawley rat pups at postnatal day 7 were randomly assigned to a control group and an experimental group. Under same conditions, the experimental group was treated with 2.8% sevoflurane for 4 hours, while the control group was exposed to air for the same time. Hippocampal tissue was extracted after 6 h. Western blot was used to detect the change of NLPR3, GSDMD, GSDMD-N, IL-18, and IL-1β pyroptotic protein（n=6）. The other rats after exposure were kept with their mothers. The open field test was performed on postnatal days 30 and the fear conditioning test was performed on postnatal days 33-34 （n=10）. Results Compared with the control group, the pyroptotic protein of NLPR3, GSDMD, GSDMD-N, IL-1β, and IL-18 in hippocampal tissues of the experimental group significantly increased（P<0.001）, the fear conditioning test showed a decreased percentage（P<0.001） of freezing time, the open field test showed no difference（P>0.05）in locomotor activity by the total distance and time spent in the center. Conclusion The sevoflurane-induced long-term memory impairment in neonatal rats may be caused by pyroptotic neuron death.

Key words: sevoflurane, neuroinflammation, pyroptosis, cognitive function

中图分类号:

R614

余帅珑, 曹冬, 马琳云, 李玉娟. 围术期全麻药七氟烷对新生大鼠远期记忆损害和神经细胞焦亡的影响[J]. 岭南现代临床外科, 2023, 23(01): 75-79.

YU Shuai-long, CAO Dong, MA Lin-yun, LI Yu-juan. Effects of perioperative general anesthetic sevoflurane on long-term memory impairment and neuronal pyroptosis in neonatal rats[J]. Lingnan Modern Clinics In Surgery, 2023, 23(01): 75-79.

参考文献

[1] Sun M, Xie Z, Zhang J, Leng Y.Mechanistic insight into sevoflurane-associated developmental neurotoxicity[J]. Cell Biol Toxicol, 2021, 38(6): 927-943.
[2] Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia[J]. Pediatrics, 2012, 130(3): e476-485.
[3] Walkden GJ, Gill H, Davies NM, et al.Early Childhood General Anesthesia and Neurodevelopmental Outcomes in the Avon Longitudinal Study of Parents and Children Birth Cohort[J]. Anesthesiology, 2020, 133(5): 1007-1020.
[4] Liu X, Xia S, Zhang Z, et al.Channelling inflammation: gasdermins in physiology and disease[J]. Nat Rev Drug Discov, 2021, 20(5): 384-405.
[5] Kesavardhana S, Malireddi RKS, Kanneganti TD.Caspases in Cell Death, Inflammation, and Pyroptosis[J]. Annu Rev Immunol, 2020, 38: 567-595.
[6] Swanson KV, Deng M, Ting JP.The NLRP3 inflammasome: molecular activation and regulation to therapeutics[J]. Nat Rev Immunol, 2019, 19(8): 477-489.
[7] Wei X, Xie F, Zhou X, et al.Role of pyroptosis in inflammation and cancer[J]. Cell Mol Immunol, 2022, 19(9): 971-992.
[8] Orning P, Lien E, Fitzgerald KA.Gasdermins and their role in immunity and inflammation[J]. J Exp Med, 2019, 216(11): 2453-2465.
[9] Fricker M, Tolkovsky AM, Borutaite V, et al.Neuronal Cell Death[J]. Physiol Rev, 2018, 98(2): 813-880.
[10] Moujalled D, Strasser A, Liddell JR.Molecular mechanisms of cell death in neurological diseases[J]. Cell Death Differ, 2021, 28(7): 2029-2044.
[11] Andropoulos DB, Greene MF.Anesthesia and Developing Brains-Implications of the FDA Warning[J]. N Engl J Med, 2017, 376(10): 905-907.
[12] Liang L, Zeng T, Zhao Y, et al.Melatonin pretreatment alleviates the long-term synaptic toxicity and dysmyelination induced by neonatal Sevoflurane exposure via MT1 receptor-mediated Wnt signaling modulation[J]. J Pineal Res, 2021, 71(4): e12771.
[13] Cornelissen L, Kim SE, Purdon PL, et al.Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants[J]. Elife, 2015, 4: e06513.
[14] Zhang L, Xue Z, Liu Q, et al.Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN[J]. EBioMedicine, 2019, 43: 473-486.
[15] Wali B, Sayeed I, Stein DG, Raper J.Prophylactic progesterone prevents adverse behavioural and neurocognitive effects of neonatal anaesthesia exposure in rat[J]. Br J Anaesth, 2022, 128(2): 301-310.
[16] Zhou X, Xu X, Lu D, et al.Repeated early-life exposure to anaesthesia and surgery causes subsequent anxiety-like behaviour and gut microbiota dysbiosis in juvenile rats[J]. Br J Anaesth, 2023, 130(2): 191-201.
[17] Yu Y, Yang Y, Tan H, et al.Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice[J]. Anesthesiology, 2020, 133(3): 595-610.
[18] Huffman WJ, Subramaniyan S, Rodriguiz RM, et al.Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice[J]. Brain Stimul, 2019, 12(1): 19-29.
[19] Zheng B, Lai R, Li J, Zuo Z.Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery[J]. Brain Behav Immun, 2017, 61: 365-374.
[20] Tan MS, Tan L, Jiang T, et al.Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer′s disease[J]. Cell Death Dis, 2014, 5(8): e1382.
[21] Deets KA, Vance RE.Inflammasomes and adaptive immune responses[J]. Nat Immunol, 2021, 22(4): 412-422.
[22] Liu Y, Liu T, Zhou Y, et al.Impeding the combination of astrocytic ASCT2 and NLRP3 by talniflumate alleviates neuroinflammation in experimental models of Parkinson′s disease[J]. Acta Pharmaceutica Sinica B, 2023, 13(2): 662-677.
[23] Li S, Fang Y, Zhang Y, et al.Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice[J]. Cell Rep, 2022, 41(4): 111532.
[24] Ising C, Venegas C, Zhang S, et al.NLRP3 inflammasome activation drives tau pathology[J]. Nature, 2019, 575(7784): 669-673.
[25] Fan Y, Du L, Fu Q, et al.Inhibiting the NLRP3 Inflammasome With MCC950 Ameliorates Isoflurane-Induced Pyroptosis and Cognitive Impairment in Aged Mice[J]. Front Cell Neurosci, 2018, 12: 426.
[26] Dai J, Li X, Wang C, et al.Repeated neonatal sevoflurane induced neurocognitive impairment through NF-κB-mediated pyroptosis[J]. J Neuroinflammation, 2021, 18(1): 180.
[27] Shao F.Gasdermins: making pores for pyroptosis[J]. Nat Rev Immunol, 2021, 21(10): 620-621.
[28] Fu Q, Wu J, Zhou XY, et al.NLRP3/Caspase-1 Pathway-Induced Pyroptosis Mediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy[J]. Inflammation, 2019, 42(1): 306-318.
[29] Dai Z, Chen XY, An LY, et al.Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse Colitis[J]. J Med Chem, 2021, 64(1): 871-889.