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Open Access 26-12-2023 | Tibia Fracture | Research Article

Anesthesia/surgery-induced learning and memory dysfunction by inhibiting mitophagy-mediated NLRP3 inflammasome inactivation in aged mice

Authors: Jian Lu, Youming Zong, Xiaoyan Tao, Hongyu Dai, Jiale Song, Hongmei Zhou

Published in: Experimental Brain Research | Issue 2/2024

Abstract

Postoperative cognitive dysfunction (POCD) is a common postoperative complication, not only affects the quality of life of the elderly and increases the mortality rate, but also brings a greater burden to the family and society. Previous studies demonstrated that Nod-like receptor protein 3 (NLRP3) inflammasome participates in various inflammatory and neurodegenerative diseases. However, possible mitophagy mechanism in anesthesia/surgery-elicited NLRP3 inflammasome activation remains to be elucidated. Hence, this study clarified whether mitophagy dysfunction is related to anesthesia/surgery-elicited NLRP3 inflammasome activation. POCD model was established in aged C57BL/6 J mice by tibial fracture fixation under isoflurane anesthesia. Morris Water Maze (MWM) was used to evaluate learning and memory abilities. We found that in vitro experiments, lipopolysaccharide (LPS) significantly facilitated NLRP3 inflammasome activation and mitophagy inhibition in BV2 cells. Rapamycin restored mitophagy and improved mitochondrial function, and inhibited NLRP3 inflammasome activation induced by LPS. In vivo experiments, anesthesia and surgery caused upregulation of hippocampal NLRP3, caspase recruitment domain (ASC) and interleukin-1β (IL-1 β), and downregulation of microtubule-associated protein light chain 3II (LC3II) and Beclin1 in aged mice. Olaparib inhibited anesthesia/surgery-induced NLRP3, ASC, and IL-1β over-expression in the hippocampus, while upregulated the expression of LC3II and Beclin1. Furthermore, Olaparib improved cognitive impairment in older mice. These results revealed that mitophagy was involved in NLRP3 inflammasome-mediated anesthesia/surgery-induced cognitive deficits in aged mice. Overall, our results suggested that mitophagy was related in NLRP3 inflammasome-induced cognitive deficits after anesthesia and surgery in aged mice. Activating mitophagy may have clinical benefits in the prevention of cognitive impairment induced by anesthesia and surgery in elderly patients.

Berger M, Nadler JW, Browndyke J, Terrando N, Ponnusamy V, Cohen HJ, Whitson HE, Mathew JP (2015) Postoperative cognitive dysfunction: minding the gaps in our knowledge of a common postoperative complication in the elderly. Anesthesiol Clin 33(3):517–550. https://doi.org/10.1016/j.anclin.2015.05.008CrossRefPubMedPubMedCentral

Bilotta F, Doronzio A, Stazi E, Titi L, Fodale V, Di Nino G, Rosa G (2010) Postoperative cognitive dysfunction: toward the Alzheimer’s disease pathomechanism hypothesis. J Alzheimer’s Dis 22(Suppl 3):81–89. https://doi.org/10.3233/JAD-2010-100825CrossRef

Chang YP, Ka SM, Hsu WH, Chen A, Chao LK, Lin CC et al (2015) Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy. J Cell Physiol 230(7):1567–1579. https://doi.org/10.1002/jcp.24903CrossRefPubMed

Chang R, Tang Y, Jia H, Dong Z, Gao S, Song Q, Dong H, Xu Q, Jiang Q, Loor JJ, Sun X, Xu C (2022) Activation of PINK1-mediated mitophagy protects bovine mammary epithelial cells against lipopolysaccharide-induced mitochondrial and inflammatory damage in vitro. Free Rad Biol Med 194:172–183. Advance online publication. https://doi.org/10.1016/j.freeradbiomed.2022.11.044

Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, Oh ES, Crosby G, Berger M, Eckenhoff RG, Nomenclature Consensus Working Group (2018) Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. British J Anaesth 121(5):1005–1012. https://doi.org/10.1016/j.bja.2017.11.087CrossRef

Feng X, Valdearcos M, Uchida Y, Lutrin D, Maze M, Koliwad SK (2017) Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight 2:e91229. https://doi.org/10.1172/jci.insight.91229CrossRefPubMedPubMedCentral

Gao S, Zhang S, Zhou H, Tao X, Ni Y, Pei D, Kang S, Yan W, Lu J (2021) Role of mTOR-regulated autophagy in synaptic plasticity related proteins downregulation and the reference memory deficits induced by anesthesia/surgery in aged mice. Front Aging Neurosci 13:628541. https://doi.org/10.3389/fnagi.2021.628541CrossRefPubMedPubMedCentral

Goldmann T, Tay TL, Prinz M (2013) Love and death: microglia, NLRP3 and the Alzheimer’s brain. Cell Res 23(5):595–596. https://doi.org/10.1038/cr.2013.24CrossRefPubMedPubMedCentral

Harris J, Deen N, Zamani S, Hasnat MA (2018) Mitophagy and the release of inflammatory cytokines. Mitochondrion 41:2–8. https://doi.org/10.1016/j.mito.2017.10.009CrossRefPubMed

He Q, Li Z, Meng C, Wu J, Zhao Y, Zhao J (2019) Parkin-dependent mitophagy is required for the inhibition of ATF4 on NLRP3 inflammasome activation in cerebral ischemia-reperfusion injury in rats. Cells 8(8):897. https://doi.org/10.3390/cells8080897CrossRefPubMedPubMedCentral

Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–678. https://doi.org/10.1038/nature11729CrossRefPubMed

Holmgaard F, Vedel AG, Rasmussen LS, Paulson OB, Nilsson JC, Ravn HB (2019) The association between postoperative cognitive dysfunction and cerebral oximetry during cardiac surgery: a secondary analysis of a randomised trial. Br J Anaesth 123(2):196–205. https://doi.org/10.1016/j.bja.2019.03.045CrossRefPubMedPubMedCentral

Lamkanfi M, Dixit VM (2014) Mechanisms and functions of inflammasomes. Cell 157(5):1013–1022. https://doi.org/10.1016/j.cell.2014.04.007CrossRefPubMed

Li Z, Zhu Y, Kang Y, Qin S, Chai J (2022) Neuroinflammation as the underlying mechanism of postoperative cognitive dysfunction and therapeutic strategies. Front Cell Neurosci 16:843069. https://doi.org/10.3389/fncel.2022.843069CrossRefPubMedPubMedCentral

Liu X, Yu Y, Zhu S (2018) Inflammatory markers in postoperative delirium (POD) and cognitive dysfunction (POCD): a meta-analysis of observational studies. PLoS ONE 13(4):e0195659. https://doi.org/10.1371/journal.pone.0195659CrossRefPubMedPubMedCentral

Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297(5868):681–683. https://doi.org/10.1038/297681a0CrossRefPubMed

Qiu LL, Luo D, Zhang H, Shi YS, Li YJ, Wu D et al (2016a) Nox-2-mediated phenotype loss of hippocampal parvalbumin interneurons might contribute to postoperative cognitive decline in aging mice. Front Aging Neurosci 8:234. https://doi.org/10.3389/fnagi.2016.00234CrossRefPubMedPubMedCentral

Qiu LL, Ji MH, Zhang H, Yang JJ, Sun XR, Tang H, Wang J, Liu WX, Yang JJ (2016b) NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in postoperative cognitive dysfunction in aged mice. Brain Behav Immun 51:109–118. https://doi.org/10.1016/j.bbi.2015.08.002CrossRefPubMed

Qiu J, Chen Y, Zhuo J, Zhang L, Liu J, Wang B et al (2022) Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson’s disease model. Neuropharmacology 207:108963. https://doi.org/10.1016/j.neuropharm.2022.108963CrossRefPubMed

Quan C, Chen J, Luo Y, Zhou L, He X, Liao Y, Chou J, Guo Q, Chen AF, Wen O (2019) BIS-guided deep anesthesia decreases short-term postoperative cognitive dysfunction and peripheral inflammation in elderly patients undergoing abdominal surgery. Brain Behav 9(4):e01238. https://doi.org/10.1002/brb3.1238CrossRefPubMedPubMedCentral

Sendler M, van den Brandt C, Glaubitz J, Wilden A, Golchert J, Weiss FU et al (2020) NLRP3 inflammasome regulates development of systemic inflammatory response and compensatory anti-inflammatory response syndromes in mice with acute pancreatitis. Gastroenterology 158(1):253-269.e14. https://doi.org/10.1053/j.gastro.2019.09.040CrossRefPubMed

Shao S, Xu CB, Chen CJ, Shi GN, Guo QL, Zhou Y et al (2021) Divanillyl sulfone suppresses NLRP3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice. J Neuroinflamm 18(1):142. https://doi.org/10.1186/s12974-021-02178-zCrossRef

Steinmetz J, Rasmussen LS (2016) Peri-operative cognitive dysfunction and protection. Anaesthesia 71(Suppl 1):58–63. https://doi.org/10.1111/anae.13308CrossRefPubMed

Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS, ISPOCD Group (2009) Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110(3):548–555. https://doi.org/10.1097/ALN.0b013e318195b569CrossRefPubMed

Su D, Zhao Y, Wang B, Li W, Xiao J, Chen J, Wang X (2011) Repeated but not single isoflurane exposure improved the spatial memory of young adult mice. Acta Anaesthesiol Scand 55(4):468–473. https://doi.org/10.1111/j.1399-6576.2010.02385CrossRefPubMed

Subramaniyan S, Terrando N (2019) Neuroinflammation and perioperative neurocognitive disorders. Anesth Analg 128(4):781–788. https://doi.org/10.1213/ANE.0000000000004053CrossRefPubMedPubMedCentral

Sun L, Yong Y, Wei P, Wang Y, Li H, Zhou Y et al (2022) Electroacupuncture ameliorates postoperative cognitive dysfunction and associated neuroinflammation via NLRP3 signal inhibition in aged mice. CNS Neurosci Ther 28(3):390–400. https://doi.org/10.1111/cns.13784CrossRefPubMed

Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1(2):848–858. https://doi.org/10.1038/nprot.2006.116CrossRefPubMedPubMedCentral

Wang Z, Meng S, Cao L, Chen Y, Zuo Z, Peng S (2018) Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment. J Neuroinflammation 15(1):109. https://doi.org/10.1186/s12974-018-1137-1CrossRefPubMedPubMedCentral

Wang XF, Lin Q, Wang GH, Zhan GM, Liu W, Lin ZW (2022) Electroacupuncture stimulation suppresses postoperative inflammatory response and hippocampal neuronal injury. Mediators Inflamm 2022:3288262. https://doi.org/10.1155/2022/3288262CrossRefPubMedPubMedCentral

Wei P, Yang F, Zheng Q, Tang W, Li J (2019) The potential role of the NLRP3 inflammasome activation as a link between mitochondria ROS generation and neuroinflammation in postoperative cognitive dysfunction. Front Cell Neurosci 13:73. https://doi.org/10.3389/fncel.2019.00073CrossRefPubMedPubMedCentral

Xu Y, Wang J, Xu W, Ding F, Ding W (2019) Prohibitin 2-mediated mitophagy attenuates renal tubular epithelial cells injury by regulating mitochondrial dysfunction and NLRP3 inflammasome activation. Am J Physiol Renal Physiol 316(2):F396–F407. https://doi.org/10.1152/ajprenal.00420.2018CrossRefPubMed

Yamano K, Matsuda N, Tanaka K (2016) The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation. EMBO Rep 17(3):300–316. https://doi.org/10.15252/embr.201541486CrossRefPubMedPubMedCentral

Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Münzberg H, Rosen CJ, Ingram DK, Salbaum JM, Dixit VD (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 18(4):519–532. https://doi.org/10.1016/j.cmet.2013.09.010CrossRefPubMedPubMedCentral

Zhao Y, Huang L, Xu H, Wu G, Zhu M, Tian J et al (2016) Neuroinflammation induced by surgery does not impair the reference memory of young adult mice. Mediators Inflamm 2016:3271579. https://doi.org/10.1155/2016/3271579CrossRefPubMedPubMedCentral

Zhao S, Chen F, Wang D, Han W, Zhang Y, Yin Q (2021) NLRP3 inflammasomes are involved in the progression of postoperative cognitive dysfunction: from mechanism to treatment. Neurosurg Rev 44(4):1815–1831. https://doi.org/10.1007/s10143-020-01387-zCrossRefPubMed

Zheng S, Jian D, Gan H, Wang L, Zhao J, Zhai X (2021) FUNDC1 inhibits NLRP3-mediated inflammation after intracerebral hemorrhage by promoting mitophagy in mice. Neurosci Lett 756:135967. https://doi.org/10.1016/j.neulet.2021.135967CrossRefPubMed

Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J et al (2016) NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164(5):896–910. https://doi.org/10.1016/j.cell.2015.12.057CrossRefPubMedPubMedCentral

Title: Anesthesia/surgery-induced learning and memory dysfunction by inhibiting mitophagy-mediated NLRP3 inflammasome inactivation in aged mice
Authors: Jian Lu
Youming Zong
Xiaoyan Tao
Hongyu Dai
Jiale Song
Hongmei Zhou
Publication date: 26-12-2023
Publisher: Springer Berlin Heidelberg
Keyword: Tibia Fracture
Published in: Experimental Brain Research / Issue 2/2024
Print ISSN: 0014-4819
Electronic ISSN: 1432-1106
DOI: https://doi.org/10.1007/s00221-023-06724-4

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Anesthesia/surgery-induced learning and memory dysfunction by inhibiting mitophagy-mediated NLRP3 inflammasome inactivation in aged mice

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