MiR-214-3p Prevents the Development of Perioperative Neurocognitive Disorders in Elderly Rats

Abstract

Objective

This study aimed to identify microRNAs (miRNAs) involved in the development of perioperative neurocognitive disorders (PND).

Methods

Plasma exosomal miRNA expression was examined in patients before and after cardiopulmonary bypass (CPB) using microarray and qRT-PCR and these patients were diagnosed as PND later. Elderly rats were subjected to CPB, and the cognitive functions were examined. Bioinformatics analysis was conducted to predict the targets of miR-214-3p. Rats were administered rno-miR-214-3p agomir before or after CPB to investigate the role of miR-214-3p in PND development.

Results

We identified 76 differentially expressed plasma exosomal miRNAs in PND patients after surgery (P<0.05, ∣log2FC∣>0.58), including the upregulated hsa-miR-214-3p (P=0.002399392). Prostaglandin-endoperoxide synthase 2 (PTGS2) was predicted as a miR-214-3p target. In rats, CPB reduced the platform crossing numbers and target quadrant stay time, accompanied with hippocampal neuronal necrosis. The rno-miR-214-3p level was significantly increased in plasma exosomes but decreased in rat hippocampus after surgery, exhibiting a negative correlation (P<0.001, r=−0.762). A negative correlation between miR-214-3p and PTGS2 protein expression was also observed in the hippocampus after surgery. Importantly, rno-miR-214-3p agomir treatment, before or after surgery, significantly increased the platform crossing numbers (P=0.035) and target quadrant stay time (P=0.029) compared with negative control. Hippocampal PTGS2 protein level was increased in the untreated surgery group and decreased in response to rno-miR-214-3p agomir treatment before or after surgery (both P<0.05 vs. negative control).

Conclusion

These data suggest that miR-214-3p/PTGS2 signaling contributes to the development of PND, serving as a potential therapeutic target for PND.

Keywords

perioperative neurocognitive disorders / exosome / hippocampus / miR-214-3p / prostaglandin-endoperoxide synthase 2

References

[1] FanW, MaiL, ZhuX, et al.. The Role of Microglia in Perioperative Neurocognitive Disorders. Front Cell Neurosci, 2020, 14: 261

[2] EveredL, SilbertB, KnopmanD, et al.. Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery-2018. Anesthesiology, 2018, 129(5): 872-879

[3] BooneMD, SitesB, von RecklinghausenFM, et al.. Economic Burden of Postoperative Neurocognitive Disorders Among US Medicare Patients. JAMA Netw Open, 2020, 3(7): e208931

[4] SkvarcD, BerkM, ByrneL, et al.. Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies. Neurosci Biobehav Rev, 2018, 84: 116-133

[5] RasmussenLS. Postoperative cognitive dysfunction: incidence and prevention. Best Pract Res Clin Anaesthesiol, 2006, 20(2): 315-330

[6] NewfieldP. Postoperative cognitive dysfunction. F1000 Med Rep, 2009, 1: 14

[7] McDonaghDL, MathewJP, WhiteWD, et al.. Cognitive function after major noncardiac surgery, apolipoprotein E4 genotype, and biomarkers of brain injury. Anesthesiology, 2010, 112(4): 852-859

[8] EckenhoffRG, MazeM, XieZ, et al.. Perioperative Neurocognitive Disorder: State of the Preclinical Science. Anesthesiology, 2020, 132(1): 55-68

[9] ChenL, DongR, LuY, et al.. MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice. Brain Behav Immun, 2019, 78: 188-201

[10] SubramaniyanS, TerrandoN. Neuroinflammation and Perioperative Neurocognitive Disorders. Anesth Analg, 2019, 128(4): 781-788

[11] SlotaJA, BoothSA. MicroRNAs in Neuroinflammation: Implications in Disease Pathogenesis, Biomarker Discovery and Therapeutic Applications. Noncoding RNA, 2019, 5(2): 35

[12] GuoY, HongW, WangX, et al.. MicroRNAs in Microglia: How do MicroRNAs Affect Activation, Inflammation, Polarization of Microglia and Mediate the Interaction Between Microglia and Glioma?. Front Mol Neurosci, 2019, 12: 125

[13] YuX, LiuS, LiJ, et al.. MicroRNA-572 improves early post-operative cognitive dysfunction by down-regulating neural cell adhesion molecule 1. PLoS One, 2015, 10(2): e0118511

[14] LiuQ, HouA, ZhangY, et al.. MiR-190a potentially ameliorates postoperative cognitive dysfunction by regulating Tiam1. BMC Genomics, 2019, 20(1): 670

[15] RajmanM, SchrattG. MicroRNAs in neural development: from master regulators to fine-tuners. Development (Cambridge, England), 2017, 144(13): 2310-2322

[16] YılmazŞ, ErdalM, ÖzgeA, et al.. Can Peripheral MicroRNA Expression Data Serve as Epigenomic (Upstream) Biomarkers of Alzheimer’s Disease?. OMICS, 2016, 20(8): 456-461

[17] NieC, SunY, ZhenH, et al.. Differential Expression of Plasma Exo-miRNA in Neurodegenerative Diseases by Next-Generation Sequencing. Front Neurosci, 2020, 14: 438

[18] SilvestroS, BramantiP, MazzonE. Role of miRNAs in Alzheimer’s Disease and Possible Fields of Application. Int J Mol Sci, 2019, 20(16): 3979

[19] AngelucciF, CechovaK, ValisM, et al.. MicroRNAs in Alzheimer’s Disease: Diagnostic Markers or Therapeutic Agents?. Front Pharmacol, 2019, 10: 665

[20] DorvalV, NelsonP, HébertS. Circulating microRNAs in Alzheimer’s disease: the search for novel biomarkers. Front Mol Neurosci, 2013, 6: 24

[21] MicciM, KrishnanB, BishopE, et al.. Hippocampal stem cells promotes synaptic resistance to the dysfunctional impact of amyloid beta oligomers via secreted exosomes. Mol Neurodegener, 2019, 14(1): 25

[22] HillA. Extracellular Vesicles and Neurodegenerative Diseases. J Neurosci, 2019, 39(47): 9269-9273

[23] Gámez-ValeroA, CampdelacreuJ, VilasD, et al.. Exploratory study on microRNA profiles from plasma-derived extracellular vesicles in Alzheimer’s disease and dementia with Lewy bodies. Transl Neurodegener, 2019, 8: 31

[24] ColemanB, HillA. Extracellular vesicles—Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Semin Cell Dev Biol, 2015, 40: 89-96

[25] DuanX, ZhuT, ChenC, et al.. Serum glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction after surgery for rheumatic heart disease. J Thorac Cardiovasc Surg, 2018, 155(3): 958-965.e951

[26] JungMK, MunJY. Sample Preparation and Imaging of Exosomes by Transmission Electron Microscopy. J Vis Exp, 2018, 131: 56482

[27] GaoZ, LiZ, DengR, et al.. Dexmedetomidine improves postoperative neurocognitive disorder after cardiopulmonary bypass in rats. Neurol Res, 2021, 43(2): 164-172

[28] TerrandoN, YangT, WangX, et al.. Systemic HMGB1 Neutralization Prevents Postoperative Neurocognitive Dysfunction in Aged Rats. Front Immunol, 2016, 7: 441

[29] WuC, WangR, LiX, et al.. Preoperative Serum MicroRNA-155 Expression Independently Predicts Postoperative Cognitive Dysfunction After Laparoscopic Surgery for Colon Cancer. Med Sci Monit, 2016, 22: 4503-4508

[30] BenderA, SullivanB, LillisL, et al.. Enzymatic and Chemical-Based Methods to Inactivate Endogenous Blood Ribonucleases for Nucleic Acid Diagnostics. J Mol Diagn, 2020, 22(8): 1030-1040

[31] GeX, GuoM, HuT, et al.. Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI. Mol Ther, 2020, 28(2): 503-522

[32] FengX, ValdearcosM, UchidaY, et al.. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight, 2017, 2(7): e91229

[33] ChenY, SunJ, ChenW, et al.. miR-124/VAMP3 is a novel therapeutic target for mitigation of surgical trauma-induced microglial activation. Signal Transduct Target Ther, 2019, 4(1): 27

[34] LiA, TongL, XuN, et al.. miR-124 regulates cerebromicrovascular function in APP/PS1 transgenic mice via C1ql3. Brain Res Bull, 2019, 153: 214-222

[35] ZhouY, GeY, LiuQ, et al.. LncRNA BACE1-AS Promotes Autophagy-Mediated Neuronal Damage Through The miR-214-3p/ATG5 Signalling Axis In Alzheimer’s Disease. Neuroscience, 2020, 455: 52-64

[36] MelliosN, FeldmanD, SheridanS, et al.. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry, 2018, 23(4): 1051-1065

[37] BahlakehG, GorjiA, SoltaniH, et al.. MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models. J Cell Physiol, 2021, 236(2): 806-823

[38] ForeroA, KuH, MalpartidaA, et al.. Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function. Neuropharmacology, 2020, 168: 108018

[39] BorrieS, BremsH, LegiusE, et al.. Cognitive Dysfunctions in Intellectual Disabilities: The Contributions of the Ras-MAPK and PI3K-AKT-mTOR Pathways. Ann Rev Genomics Hum Genet, 2017, 18: 115-142

[40] MartinP, StanleyR, RossA, et al.. DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling. Mol Psychiatry, 2018, 23(2): 467-475

[41] ArdahM, BharathanG, KitadaT, et al.. Ellagic Acid Prevents Dopamine Neuron Degeneration from Oxidative Stress and Neuroinflammation in MPTP Model of Parkinson’s Disease. Biomolecules, 2020, 10(11): 519

[42] LeeJY, HanSH, ParkMH, et al.. N-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease. Nat Commun, 2020, 11(1): 2358

[43] WangT, ZhaiL, ZhangH, et al.. Picroside II Inhibits the MEK-ERK1/2-COX2 Signal Pathway to Prevent Cerebral Ischemic Injury in Rats. J Mol Neurosci, 2015, 57(3): 335-351

[44] HindmanB, MooreS, CutkompJ, et al.. Brain expression of inducible cyclooxygenase 2 messenger RNA in rats undergoing cardiopulmonary bypass. Anesthesiology, 2001, 95(6): 1380-1388