Abstract
The objective of this study was to discuss the possible mechanism and effect of miR-182-5p delivered by plasma exosomes on sevoflurane-induced neuroinflammation and cognitive disorder in aged rats with postoperative cognitive dysfunction (POCD). Firstly, aged POCD rat models were constructed by sevoflurane anesthesia and superior mesenteric artery occlusion. Subsequently, exosomes and miR-182-5p were inhibited by injection of GW4869 and miR-182-5p-sponge, respectively. Then, exosomes were extracted from the plasma of rats in each group, followed by the determination of the morphology and diameters of exosomes as well as the expression of exosome markers CD63 and CD81 by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Besides, the Morris water maze (MWM) and fear conditioning test were used to evaluate the learning and memory ability of rats; Western blot to detect the expression levels of neurotrophic factors (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) as well as NF-κB pathway-related proteins (p65 and p-p65) in rat hippocampal tissues or PC-12 cells; qRT-PCR to assess the expression levels of miR-182-5p and BDNF in rat plasma, plasma exosomes, hippocampal tissues, and PC-12 cells; ELISA to evaluate the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in rat hippocampal tissues; and dual-luciferase reporter assay to verify the targeting relationship between miR-182-5p and BDNF. After examination, the results were obtained as follows. miR-182-5p expression was up-regulated in POCD rats and could be delivered by plasma exosomes. Inhibition of plasma exosomes or miR-182-5p could significantly ameliorate learning and memory disorders; decrease the levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β; increase the expression of BDNF and NGF; and inhibit the activity of NF-κB signaling pathway in POCD rat hippocampus. In addition, miR-182-5p could also target and inhibit BDNF. All in all, miR-182-5p delivered by plasma exosomes promotes sevoflurane-induced neuroinflammation and cognitive dysfunction in aged POCD rats by targeting BDNF and activating the NF-κB pathway.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets used and analyzed in the current study are available from the corresponding author upon reasonable request.
References
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297. https://doi.org/10.1016/s0092-8674(04)00045-5
Cao MQ, You AB, Zhu XD, Zhang W, Zhang YY, Zhang SZ et al (2018) miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a. J Hematol Oncol 11:12. https://doi.org/10.1186/s13045-018-0555-y
Chen JJ, Zhao B, Zhao J, Li S (2017) Potential roles of exosomal microRNAs as diagnostic biomarkers and therapeutic application in Alzheimer’s disease. Neural Plast 2017:7027380. https://doi.org/10.1155/2017/7027380
Chen L, Dong R, Lu Y, Zhou Y, Li K, Zhang Z et al (2019) MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice. Brain Behav Immun 78:188–201. https://doi.org/10.1016/j.bbi.2019.01.020
Chen Y, Zhang P, Lin X, Zhang H, Miao J, Zhou Y et al (2020) Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats. Aging (Albany NY) 12:17235–17256. https://doi.org/10.18632/aging.103673
Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, Christie BR et al (2009) NGF is essential for hippocampal plasticity and learning. J Neurosci 29:10883–10889. https://doi.org/10.1523/JNEUROSCI.2594-09.2009
Deng Z, Ou H, Ren F, Guan Y, Huan Y, Cai H et al (2020) LncRNA SNHG14 promotes OGD/R-induced neuron injury by inducing excessive mitophagy via miR-182-5p/BINP3 axis in HT22 mouse hippocampal neuronal cells. Biol Res 53:38. https://doi.org/10.1186/s40659-020-00304-4
Du X, Wei J, Tian D, Wu M, Yan C, Hu P et al (2020) miR-182-5p contributes to intestinal injury in a murine model of Staphylococcus aureus pneumonia-induced sepsis via targeting surfactant protein D. J Cell Physiol 235:563–572. https://doi.org/10.1002/jcp.28995
Farazi TA, Spitzer JI, Morozov P, Tuschl T (2011) miRNAs in human cancer. J Pathol 223:102–115. https://doi.org/10.1002/path.2806
Gruenberg J, van der Goot FG (2006) Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol 7:495–504. https://doi.org/10.1038/nrm1959
Guijarro JZ, Tiba PA, Ferreira TL, Kawakami SE, Oliveira MG, Suchecki D (2007) Effects of brief and long maternal separations on the HPA axis activity and the performance of rats on context and tone fear conditioning. Behav Brain Res 184:101–108. https://doi.org/10.1016/j.bbr.2007.06.020
Henriksson BG, Soderstrom S, Gower AJ, Ebendal T, Winblad B, Mohammed AH (1992) Hippocampal nerve growth factor levels are related to spatial learning ability in aged rats. Behav Brain Res 48:15–20. https://doi.org/10.1016/s0166-4328(05)80134-2
Huang W, Cui X, Chen J, Feng Y, Song E, Li J et al (2016) Long non-coding RNA NKILA inhibits migration and invasion of tongue squamous cell carcinoma cells via suppressing epithelial-mesenchymal transition. Oncotarget 7:62520–62532. https://doi.org/10.18632/oncotarget.11528
Jia M, Liu WX, Sun HL, Chang YQ, Yang JJ, Ji MH et al (2015) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice. Front Mol Neurosci 8:52. https://doi.org/10.3389/fnmol.2015.00052
Jiang S, Miao D, Wang M, Lv J, Wang Y, Tong J (2019) MiR-30-5p suppresses cell chemoresistance and stemness in colorectal cancer through USP22/Wnt/beta-catenin signaling axis. J Cell Mol Med 23:630–640. https://doi.org/10.1111/jcmm.13968
Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K et al (2002) Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology 96:1351–1357. https://doi.org/10.1097/00000542-200206000-00014
Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T (2003) New microRNAs from mouse and human. RNA 9:175–179. https://doi.org/10.1261/rna.2146903
Li B, Arime Y, Hall FS, Uhl GR, Sora I (2010) Impaired spatial working memory and decreased frontal cortex BDNF protein level in dopamine transporter knockout mice. Eur J Pharmacol 628:104–107. https://doi.org/10.1016/j.ejphar.2009.11.036
Li C, Lie H, Sun W (2022) Inhibitory effect of miR1825p on retinal neovascularization by targeting angiogenin and BDNF. Mol Med Rep 25. https://doi.org/10.3892/mmr.2021.12577
Li M, Zhang J, Zhang HX (2016) Effects of PPARγ activators on neurobehavioral functions in rats with hypoxic-ischemic brain injury. Chin J Gerontol 36:1582–1584
Luo J, Shi K, Yin SY, Tang RX, Chen WJ, Huang LZ et al (2018) Clinical value of miR-182-5p in lung squamous cell carcinoma: a study combining data from TCGA, GEO, and RT-qPCR validation. World J Surg Oncol 16:76. https://doi.org/10.1186/s12957-018-1378-6
McGeary SE, Lin KS, Shi CY, Pham TM, Bisaria N, Kelley GM et al (2019) The biochemical basis of microRNA targeting efficacy. Science 366.https://doi.org/10.1126/science.aav1741
Monk TG, Price CC (2011) Postoperative cognitive disorders. Curr Opin Crit Care 17:376–381. https://doi.org/10.1097/MCC.0b013e328348bece
Needham MJ, Webb CE, Bryden DC (2017) Postoperative cognitive dysfunction and dementia: what we need to know and do. Br J Anaesth 119:i115–i125. https://doi.org/10.1093/bja/aex354
Oberg AL, French AJ, Sarver AL, Subramanian S, Morlan BW, Riska SM et al (2011) miRNA expression in colon polyps provides evidence for a multihit model of colon cancer. PLoS ONE 6:e20465. https://doi.org/10.1371/journal.pone.0020465
Punjasawadwong Y, Chau-In W, Laopaiboon M, Punjasawadwong S, Pin-On P (2018) Processed electroencephalogram and evoked potential techniques for amelioration of postoperative delirium and cognitive dysfunction following non-cardiac and non-neurosurgical procedures in adults. Cochrane Database Syst Rev 5:CD011283. https://doi.org/10.1002/14651858.CD011283.pub2
Rudolph JL, Schreiber KA, Culley DJ, McGlinchey RE, Crosby G, Levitsky S et al (2010) Measurement of post-operative cognitive dysfunction after cardiac surgery: a systematic review. Acta Anaesthesiol Scand 54:663–677. https://doi.org/10.1111/j.1399-6576.2010.02236.x
Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16:203–222. https://doi.org/10.1038/nrd.2016.246
Sato-Kuwabara Y, Melo SA, Soares FA, Calin GA (2015) The fusion of two worlds: non-coding RNAs and extracellular vesicles–diagnostic and therapeutic implications (Review). Int J Oncol 46:17–27. https://doi.org/10.3892/ijo.2014.2712
Shen YN, Du JY, Pan CL, Cai MM, Si YN, Bao HG (2021) Sevoflurane activates hippocampal mitophagy and thereby induces cognitive decline in aged mice. J Clin Anesth 37:180–185. https://doi.org/10.12089/jca.2021.02.015
Steinmetz J, Funder KS, Dahl BT, Rasmussen LS (2010) Depth of anaesthesia and post-operative cognitive dysfunction. Acta Anaesthesiol Scand 54:162–168. https://doi.org/10.1111/j.1399-6576.2009.02098.x
Sun Q, Yu Y, Liu L, Wu B, Yan ES, Yin N (2019) Application of sevoflurane inhalation anesthesia without intubation in day surgery of pediatric density. J Clin Anesth 35:773–775. https://doi.org/10.12089/jca.2019.08.011
Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK et al (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481:243–268. https://doi.org/10.1016/s0027-5107(01)00183-x
Tian XS, Tong YW, Li ZQ, Li LX, Zhang T, Ren TY et al (2015) Surgical stress induces brain-derived neurotrophic factor reduction and postoperative cognitive dysfunction via glucocorticoid receptor phosphorylation in aged mice. CNS Neurosci Ther 21:398–409. https://doi.org/10.1111/cns.12368
Wang AT, Yao SL, Bao NRS, Wu N, Guo DM, Tie ME (2020) Effects of sevoflurane on expression of fractalkine and CX3CR1 and learning and memory function in developing mouse brain. J Clin Anesth 36:63–67
Wang F, Wu D, Xu Z, Chen J, Zhang J, Li X et al (2019) miR-182-5p affects human bladder cancer cell proliferation, migration and invasion through regulating Cofilin 1. Cancer Cell Int 19:42. https://doi.org/10.1186/s12935-019-0758-5
Wei C, Sun Y, Wang J, Lin D, Cui V, Shi H et al (2021) LncRNA NONMMUT055714 acts as the sponge of microRNA-7684–5p to protect against postoperative cognitive dysfunction. Aging (Albany NY) 13:12552–12564. https://doi.org/10.18632/aging.202932
Wu X, Wang W, Wu G, Peng C, Liu J (2021) miR-182-5p Serves as an oncogene in lung adenocarcinoma through binding to STARD13. Comput Math Methods Med 2021:7074343. https://doi.org/10.1155/2021/7074343
Yang F, Liao X, Tian Y, Li G (2017) Exosome separation using microfluidic systems: size-based, immunoaffinity-based and dynamic methodologies. Biotechnol J 12.https://doi.org/10.1002/biot.201600699
Yang X, Zhang W, Wu H, Fu S, Yang J, Liu S et al (2020a) Downregulation of CDK5 restores sevoflurane-induced cognitive dysfunction by promoting SIRT1-mediated autophagy. Cell Mol Neurobiol 40:955–965. https://doi.org/10.1007/s10571-020-00786-6
Yang ZY, Liu J, Chu HC (2020b) Effect of NMDAR-NMNAT1/2 pathway on neuronal cell damage and cognitive impairment of sevoflurane-induced aged rats. Neurol Res 42:108–117. https://doi.org/10.1080/01616412.2019.1710393
Zhang J, Wu Y (2018) microRNA-182-5p alleviates spinal cord injury by inhibiting inflammation and apoptosis through modulating the TLR4/NF-kappaB pathway. Int J Clin Exp Pathol 11:2948–2958
Zhu L, Nang C, Luo F, Pan H, Zhang K, Liu J et al (2016) Esculetin attenuates lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice. Physiol Behav 163:184–192. https://doi.org/10.1016/j.physbeh.2016.04.051
Funding
This study is supported by the Jiangxi Provincial Science Department (20202BABL206048).
Author information
Authors and Affiliations
Contributions
Fu-sheng Wei and Lei Yang wrote the paper and conceived and designed the experiments; Mu-wen Rao and Yuan-lu Huang analyzed the data. Shi-biao Chen and Yu-qian Wu collected and provided the sample for this study. All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Ethical Approval
The study was approved by the Ethics Committee of The First Affiliated Hospital of Nanchang University [2021-(9-015)] and conducted following the approved guidelines.
Conflict of Interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wei, Fs., Rao, Mw., Huang, Yl. et al. miR-182-5p Delivered by Plasma Exosomes Promotes Sevoflurane-Induced Neuroinflammation and Cognitive Dysfunction in Aged Rats with Postoperative Cognitive Dysfunction by Targeting Brain-Derived Neurotrophic Factor and Activating NF-κB Pathway. Neurotox Res 40, 1902–1912 (2022). https://doi.org/10.1007/s12640-022-00597-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-022-00597-1