Dexmedetomidine alleviates postoperative cognitive dysfunction through circular RNA in aged rats

Cao, Cao; Deng, Fumou; Hu, Yanhui

doi:10.1007/s13205-020-2163-0

Original Article
Published: 24 March 2020

Dexmedetomidine alleviates postoperative cognitive dysfunction through circular RNA in aged rats

3 Biotech volume 10, Article number: 176 (2020) Cite this article

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Abstract

Circular RNA (circRNA) has been well studied in many diseases, whereas their role in patients with postoperative cognitive dysfunction (POCD) remains largely unclear. Here, we investigated the therapeutic effects of dexmedetomidine (Dex) on POCD and analyzed the role of circRNA as well as the pathways that may be involved. The Morris water maze test demonstrated that POCD rats have a longer incubation period than the normal group, but the latency of POCD rats was significantly lower after Dex treatment. Moreover, HE staining showed that Dex improved hippocampal pathological changes. RNA sequencing showed 164 differentially expressed circRNAs between POCD and Dex groups; 74 were upregulated and 90 were downregulated in the Dex group. A total of 20,790 target genes for differentially expressed circRNAs were observed in RNAhybrid and Miranda databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the target genes of differentially expressed circRNAs are mainly focused on positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage, negative regulation of cell adhesion mediated by integrin, and response to cytokines and other function of life activities and involved in the P53 signaling pathway and nuclear factor kappa B (NF-κB) signaling pathway. Furthermore, the expression of five candidate circRNAs (circ-Shank3, circ-Cdc42bpa, circ-chrx-24658, cir-chr17-3642 and circ-Sgsm1) and target genes were consistent with the RNA sequencing results, which was verified by quantitative real-time polymerase chain reaction (qRT-PCR). These results indicate that circ-Shank3 participate in the process of Dex improved POCD through regulating the P53 and NF-κB signaling pathways and may potentially facilitate POCD treatment through the development of clinical drugs.

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References

Aufiero S, Reckman YJ, Pinto YM, Creemers EE (2019) Circular RNAs open a new chapter in cardiovascular biology. Nat Rev Cardiol 16(8):503–514. https://doi.org/10.1038/s41569-019-0185-2
Article PubMed Google Scholar
Chen B, Li Y, Liu Y, Xu Z (2019a) circLRP6 regulates high glucose-induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells. J Cell Physiol 234:21249–21259
CAS Article Google Scholar
Chen L, Wang F, Bruggeman EC, Li C, Yao B (2019b) circMeta: a unified computational framework for genomic feature annotation and differential expression analysis of circular RNAs. Bioinform 36:539–545
Google Scholar
Cho JS, Shim JK, Soh S, Kim MK, Kwak YL (2016) Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery. Kidney Int 89(3):693–700. https://doi.org/10.1038/ki.2015.306
CAS Article PubMed Google Scholar
Cooks T, Harris CC, Oren M (2014) Caught in the cross fire: p53 in inflammation. Carcinogenesis 35(8):1680–1690. https://doi.org/10.1093/carcin/bgu134
CAS Article PubMed PubMed Central Google Scholar
Fodale V, Santamaria LB, Schifilliti D, Mandal PK (2010) Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer's disease. Anaesthesia 65(4):388–395. https://doi.org/10.1111/j.1365-2044.2010.06244.x
CAS Article PubMed Google Scholar
Fu H-W, Lin X, Zhu Y-X, Lan X, Kuang Y, Wang Y-Z, Ke Z-G, Yuan T, Chen P (2019) Circ-IGF1R has pro-proliferative and anti-apoptotic effects in HCC by activating the PI3K/AKT pathway. Gene 716:144031
CAS Article Google Scholar
Gao R, Li M, Wang Q, Chen H, Yu H, Liu J, Zhu T, Chen C (2019) Identification of the potential key circrnas in elderly patients with postoperative cognitive dysfunction. http://www.asaabstracts.com/strands/asaabstracts/abstract.htm?year=2019&index=10&absnum=1799
Glumac S, Kardum G, Karanovic N (2018) A Prospective cohort evaluation of the cortisol response to cardiac surgery with occurrence of early postoperative cognitive decline. Med Sci Monit 24:977–986. https://doi.org/10.12659/msm.908251
CAS Article PubMed PubMed Central Google Scholar
Goettel N, Burkhart CS, Rossi A, Cabella BC, Berres M, Monsch AU, Czosnyka M, Steiner LA (2017) Associations between impaired cerebral blood flow autoregulation, cerebral oxygenation, and biomarkers of brain injury and postoperative cognitive dysfunction in elderly patients after major non-cardiac surgery. Anesth Analg 124(3):934–942
CAS Article Google Scholar
Hofer S, Steppan J, Wagner T, Funke B, Lichtenstern C, Martin E, Graf BM, Bierhaus A, Weigand MA (2009) Central sympatholytics prolong survival in experimental sepsis. Crit Care 13(1):R11. https://doi.org/10.1186/cc7709
Article PubMed PubMed Central Google Scholar
Hong B, Lim C, Kang H, Eom H, Kim Y, Cho HJ, Han W, Lee S, Chung W, Kim YH (2019) Thoracic Paravertebral Block with Adjuvant Dexmedetomidine in Video-Assisted Thoracoscopic Surgery: A Randomized, Double-Blind Study. J Clin Med. https://doi.org/10.3390/jcm8030352
Article PubMed PubMed Central Google Scholar
Idda ML, Munk R, Abdelmohsen K, Gorospe M (2018) Noncoding RNAs in Alzheimer's disease. Wiley Interdiscip Rev RNA. https://doi.org/10.1002/wrna.1463
Article PubMed PubMed Central Google Scholar
Jin G, Wang Q, Hu X, Li X, Pei X, Xu E, Li M (2019) Profiling and functional analysis of differentially expressed circular RNAs in high glucose-induced human umbilical vein endothelial cells. FEBS Open Biol 9(9):1640–1651. https://doi.org/10.1002/2211-5463.12709
CAS Article Google Scholar
Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2012) Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 298:229–317. https://doi.org/10.1016/B978-0-12-394309-5.00006-7
CAS Article PubMed PubMed Central Google Scholar
Kong P, Yu Y, Wang L, Dou Y-Q, Zhang X-H, Cui Y, Wang H-Y, Yong Y-T, Liu Y-B, Hu H-J (2019) circ-Sirt1 controls NF-κB activation via sequence-specific interaction and enhancement of SIRT1 expression by binding to miR-132/212 in vascular smooth muscle cells. Nucleic Acids Res 47(7):3580–3593
CAS Article Google Scholar
Kontak AC, Victor RG, Vongpatanasin W (2013) Dexmedetomidine as a novel countermeasure for cocaine-induced central sympathoexcitation in cocaine-addicted humans. Hypertension 61(2):388–394
CAS Article Google Scholar
Lei K, Bai H, Wei Z, Xie C, Wang J, Li J, Chen Q (2018) The mechanism and function of circular RNAs in human diseases. Exp Cell Res 368(2):147–158. https://doi.org/10.1016/j.yexcr.2018.05.002
CAS Article PubMed Google Scholar
Li X, Yang L, Chen LL (2018a) The biogenesis, functions, and challenges of circular RNAs. Mol Cell 71(3):428–442. https://doi.org/10.1016/j.molcel.2018.06.034
CAS Article PubMed Google Scholar
Li Y, Pan Y, Gao L, Lu G, Zhang J, Xie X, Tong Z, Li B, Li G, Li W (2018b) Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression. Biochem Biophys Res Commun 495(4):2439–2447. https://doi.org/10.1016/j.bbrc.2017.12.090
CAS Article PubMed Google Scholar
Li PJ, Guo YQ, Ding PY, Liu RB, Deng F, Feng XX, Yan WJ (2019) Neuroprotective effects of a Smoothened receptor agonist against postoperative cognitive dysfunction by promoting autophagy in the dentate gyrus of aged rats. Neurol Res 41(10):867–874. https://doi.org/10.1080/01616412.2019.1628411
CAS Article PubMed Google Scholar
Liu P-R, Zhou Y, Zhang Y, Diao S (2017) Electroacupuncture alleviates surgery-induced cognitive dysfunction by increasing α7-nAChR expression and inhibiting inflammatory pathway in aged rats. Neurosci Lett 659:1–6
CAS Article Google Scholar
Lukiw WJ (2013) Circular RNA (circRNA) in Alzheimer's disease (AD). Front Genet 4:307. https://doi.org/10.3389/fgene.2013.00307
CAS Article PubMed PubMed Central Google Scholar
Marcus MT, Walker T, Swint JM, Smith BP, Brown C, Busen N, Edwards T, Liehr P, Taylor WC, Williams D, von Sternberg K (2004) Community-based participatory research to prevent substance abuse and HIV/AIDS in African-American adolescents. J Interprof Care 18(4):347–359. https://doi.org/10.1080/13561820400011776
Article PubMed Google Scholar
Menon DV, Wang Z, Fadel PJ, Arbique D, Leonard D, Li J-L, Victor RG, Vongpatanasin W (2007) Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans. J Am Coll Cardiol 50(7):626–633
CAS Article Google Scholar
Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS, Clayton NS, Connor R, Davis S, Deakin B, DeRubeis RJ, Dubois B, Geyer MA, Goodwin GM, Gorwood P, Jay TM, Joels M, Mansuy IM, Meyer-Lindenberg A, Murphy D, Rolls E, Saletu B, Spedding M, Sweeney J, Whittington M, Young LJ (2012) Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 11(2):141–168. https://doi.org/10.1038/nrd3628
CAS Article PubMed Google Scholar
Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS (1998) Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 351(9106):857–861. https://doi.org/10.1016/s0140-6736(97)07382-0
CAS Article PubMed Google Scholar
Pang X, Zhang P, Zhou Y, Zhao J, Liu H (2020) Dexmedetomidine pretreatment attenuates isoflurane-induced neurotoxicity via inhibiting the TLR2/NF-κB signalling pathway in neonatal rats. Exp Mol Pathol 112:104328
Article Google Scholar
Park J-H, Soh S, Kwak Y-L, Kim B, Choi S, Shim J-K (2019) Anesthetic efficacy of dexmedetomidine versus midazolam when combined with remifentanil for percutaneous transluminal angioplasty in patients with peripheral artery disease. J Clin Med 8(4):472
CAS Article Google Scholar
Riquelme JA, Westermeier F, Hall AR, Vicencio JM, Pedrozo Z, Ibacache M, Fuenzalida B, Sobrevia L, Davidson SM, Yellon DM, Sanchez G, Lavandero S (2016) Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism. Pharmacol Res 103:318–327. https://doi.org/10.1016/j.phrs.2015.11.004
CAS Article PubMed Google Scholar
Sanders RD, Xu J, Shu Y, Januszewski A, Halder S, Fidalgo A, Sun P, Hossain M, Ma D, Maze M (2009) Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 110(5):1077–1085. https://doi.org/10.1097/ALN.0b013e31819daedd
CAS Article PubMed Google Scholar
Shoair OA, Grasso Ii MP, Lahaye LA, Daniel R, Biddle CJ, Slattum PW (2015) Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major non-cardiac surgery: a prospective study. J Anaesthesiol Clin Pharmacol 31(1):30–36. https://doi.org/10.4103/0970-9185.150530
Article PubMed PubMed Central Google Scholar
Vongpatanasin W, Mansour Y, Chavoshan B, Arbique D, Victor RG (1999) Cocaine stimulates the human cardiovascular system via a central mechanism of action. Circulation 100(5):497–502. https://doi.org/10.1161/01.cir.100.5.497
CAS Article PubMed PubMed Central Google Scholar
Wang M, Su P, Liu Y, Zhang X, Yan J, An X, Wang X, Gu S (2019) Abnormal expression of circRNA_089763 in the plasma exosomes of patients with post-operative cognitive dysfunction after coronary artery bypass grafting. Mol Med Rep 20(3):2549–2562
CAS PubMed PubMed Central Google Scholar
Westholm JO, Miura P, Olson S, Shenker S, Joseph B, Sanfilippo P, Celniker SE, Graveley BR, Lai EC (2014) Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep 9(5):1966–1980
CAS Article Google Scholar
Wilusz JE (2018) A 360 view of circular RNAs: from biogenesis to functions. Wiley Interdiscip Rev RNA 9(4):e1478
Article Google Scholar
Xie F, Zhao Y, Wang SD, Ma J, Wang X, Qian LJ (2019) Identification, characterization, and functional investigation of circular RNAs in subventricular zone of adult rat brain. J Cell Biochem 120(3):3428–3437. https://doi.org/10.1002/jcb.27614
CAS Article PubMed Google Scholar
Xiong B, Shi Q, Fang H (2016) Dexmedetomidine alleviates postoperative cognitive dysfunction by inhibiting neuron excitation in aged rats. Am J Transl Res 8(1):70–80
CAS PubMed PubMed Central Google Scholar
Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL (2013) Circular intronic long noncoding RNAs. Mol Cell 51(6):792–806. https://doi.org/10.1016/j.molcel.2013.08.017
CAS Article Google Scholar
Zhang J, Wang Z, Wang Y, Zhou G, Li H (2015a) The effect of dexmedetomidine on inflammatory response of septic rats. BMC Anesthesiol 15:68. https://doi.org/10.1186/s12871-015-0042-8
CAS Article PubMed PubMed Central Google Scholar
Zhang QB, Xiao-Feng LI, Neurology DO (2015b) Research advances in the pathogenesis of postoperative cognitive dysfunction. Med Recapitul
Zhang X-Y, Shan H-J, Zhang P, She C, Zhou X-Z (2018) LncRNA EPIC1 protects human osteoblasts from dexamethasone-induced cell death. Biochem Biophys Res Commun 503(4):2255–2262
CAS Article Google Scholar
Zhu C-Y, Yao C, Zhu L-Q, She C, Zhou X-Z (2019) Dexamethasone-induced cytotoxicity in human osteoblasts is associated with circular RNA HIPK3 downregulation. Biochem Biophys Res Commun 516(3):645–652
CAS Article Google Scholar

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Cao Cao and Fumou Deng contributed equally to this work.

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Department of Anesthesiology, Donghu District, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, Jiangxi, China
Cao Cao, Fumou Deng & Yanhui Hu

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Cao Cao
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Fumou Deng
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Yanhui Hu
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Contributions

YH contributed to conceptualization and funding acquisition: YH. Data curation: CC and FD. CC and FD were involved in formal analysis. CC and FD were involved in investigation. CC and FD were involved in methodology.CC and FD contributed to writing—original draft. CC and FD contributed to writing— review and editing. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Yanhui Hu.

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This study was approved by the Institutional Animal Care and Use Committee of the Second Affiliated Hospital of Nanchang University. All animal experiments were performed in accordance with the Guides for the Care and Use of Laboratory Animals.

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The authors declare that there is no conflict of interest regarding the publication of this paper.

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13205_2020_2163_MOESM1_ESM.tif

Supplementary file1 Figure S1. The expression pattern of circRNAs was examined by RNA sequencing during the Dex treatment of POCD rats. The results showed that the higher the number of exons covered, the fewer the circRNAs. (A) The statistical chart of exon number count covered by circRNAs. (B) The number of circRNAs distributed on each chromosome number. Among them, the number of circRNAs on chromosomes 1, 2, and 6 were all greater than 500.

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Cao, C., Deng, F. & Hu, Y. Dexmedetomidine alleviates postoperative cognitive dysfunction through circular RNA in aged rats. 3 Biotech 10, 176 (2020). https://doi.org/10.1007/s13205-020-2163-0

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Received: 09 January 2020
Accepted: 07 March 2020
Published: 24 March 2020
DOI: https://doi.org/10.1007/s13205-020-2163-0

Keywords

Postoperative cognitive dysfunction
Dexmedetomidine
Circular RNAs
Mechanism