Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Anesthesiology
Published in: BMC Anesthesiology 1/2023

Open Access 01-12-2023 | Research

Dexmedetomidine attenuates postoperative spatial memory impairment after surgery by reducing cytochrome C

Authors: Lina Sun, Kun Niu, Jian Guo, Jingru Tu, Baofeng Ma, Jianxiong An

Published in: BMC Anesthesiology | Issue 1/2023

Login to get access

Abstract

Background

Anesthesia and surgery can induce perioperative neurocognitive disorders (PND). Mitochondrial dysfunction has been proposed to be one of the earliest triggering events in surgery-induced neuronal damage. Dexmedetomidine has been demonstrated to attenuate the impairment of cognition in aged rats induced by surgery in our previous study.

Methods

Male Sprague-Dawley rats underwent hepatic apex resection under anesthesia with propofol to clinically mimic human abdominal surgery. The rats were divided into three groups: Control group, Model group and Dexmedetomidine (Dex) group. Cognitive function was evaluated with the Morris water maze (MWM), Open Field Test (OFT)and Novel object recognition task (NOR). Ultrastructural change in neuronal mitochondria was measured by transmission electron microscopy. Mitochondrial function was measured by mitochondrial membrane potential and activities of mitochondrial complexes. Neuronal morphology was observed with H&E staining and the activation of glial cells was observed by immunohistochemistry in the hippocampus. Protein levels were measured by Western blot (WB) and immunofluorescence at 3 and 7 days after surgery.

Results

Surgery-induced cognitive decline lasts three days, but not seven days after surgery in the model group. Transmission electron microscope showed the mitochondrial structure damage in the model group, similar changes were not induced in the Dex group. Dexmedetomidine may reverse the decrease in mitochondrial membrane potential and mitochondrial complex activity. Compared with the Control group, the expression of cytochrome c was significantly increased in model group by Western blot and immunofluorescence on days 3, but not day 7. Rats from the Model group expressed significantly greater levels of Iba-1 and GFAP compared with the Control group and the Dex group.

Conclusion

Dexmedetomidine appears to reverse surgery-induced behavior, mitigate the higher density of Iba-1 and GFAP, reduce the damage of mitochondrial structure and function by alleviating oxidative stress and protect mitochondrial respiratory chain, thus increasing cytochrome c oxidase (COX) expression and downregulate the expression of cytochrome c protein in the hippocampus of rats.
Appendix
Available only for authorised users
Literature
1.
Norkiene I, Samalavicius R, Misiuriene I, Paulauskiene K, Budrys V, Ivaskevicius J. Incidence and risk factors for early postoperative cognitive decline after coronary artery bypass grafting. Med (Kaunas). 2010;46(7):460–4.
2.
3.
Deiner S, Luo X, Lin HM, Sessler DI, Saager L, Sieber FE, Lee HB, Sano M, Jankowski C, Bergese SD, et al. Intraoperative infusion of Dexmedetomidine for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients undergoing major elective noncardiac surgery: a Randomized Clinical Trial. JAMA Surg. 2017;152(8):e171505.CrossRefPubMedPubMedCentral
4.
Skvarc DR, Berk M, Byrne LK, Dean OM, Dodd S, Lewis M, Marriott A, Moore EM, Morris G, Page RS, et al. Post-operative cognitive dysfunction: an exploration of the inflammatory hypothesis and novel therapies. Neurosci Biobehav Rev. 2018;84:116–33.CrossRefPubMed
5.
He K, Zhang J, Zhang W, Wang S, Li D, Ma X, Wu X, Chai X, Liu Q. Hippocampus-based mitochondrial respiratory function decline is responsible for Perioperative Neurocognitive Disorders. Front Aging Neurosci. 2022;14:772066.CrossRefPubMedPubMedCentral
6.
Smaili SS, Hsu YT, Carvalho AC, Rosenstock TR, Sharpe JC, Youle RJ. Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling. Braz J Med Biol Res. 2003;36(2):183–90.CrossRefPubMed
7.
Bhatia V, Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer’s disease. J Neurol Sci. 2021;421:117253.CrossRefPubMed
8.
An J, Fang Q, Huang C, Qian X, Fan T, Lin Y, Guo Q. Deeper total intravenous anesthesia reduced the incidence of early postoperative cognitive dysfunction after microvascular decompression for facial spasm. J Neurosurg Anesthesiol. 2011;23(1):12–7.CrossRefPubMed
9.
Farag E, Chelune GJ, Schubert A, Mascha EJ. Is depth of anesthesia, as assessed by the Bispectral Index, related to postoperative cognitive dysfunction and recovery? Anesth Analg. 2006;103(3):633–40.CrossRefPubMed
10.
Quan C, Chen J, Luo Y, Zhou L, He X, Liao Y, Chou J, Guo Q, Chen AF, Wen O. BIS-guided deep anesthesia decreases short-term postoperative cognitive dysfunction and peripheral inflammation in elderly patients undergoing abdominal surgery. Brain and behavior. 2019;9(4):e01238.CrossRefPubMedPubMedCentral
11.
Ma J, Williams J, Eastwood D, Lin S, Qian X, Fang Q, Cope D, Yuan Z, Cao L, An J. High-dose Propofol Anesthesia reduces the occurrence of postoperative cognitive dysfunction via maintaining Cytoskeleton. Neuroscience. 2019;421:136–43.CrossRefPubMed
12.
Niu K, Qin JL, Lu GF, Guo J, Williams JP, An JX. Dexmedetomidine reverses postoperative spatial memory deficit by targeting Surf1 and cytochrome c. Neuroscience. 2021;466:148–61.CrossRefPubMed
13.
Unchiti K, Leurcharusmee P, Samerchua A, Pipanmekaporn T, Chattipakorn N, Chattipakorn SC. The potential role of dexmedetomidine on neuroprotection and its possible mechanisms: evidence from in vitro and in vivo studies. Eur J Neurosci. 2021;54(9):7006–47.CrossRefPubMed
14.
Chen J, Shen N, Duan X, Guo Y. An investigation of the mechanism of dexmedetomidine in improving postoperative cognitive dysfunction from the perspectives of alleviating neuronal mitochondrial membrane oxidative stress and electrophysiological dysfunction. Exp Ther Med. 2018;15(2):2037–43.PubMed
15.
Ghaffary S, Ghaeli P, Talasaz AH, Karimi A, Noroozian M, Salehiomran A, Jalali A. Effect of memantine on post-operative cognitive dysfunction after cardiac surgeries: a randomized clinical trial. Daru. 2017;25(1):24.CrossRefPubMedPubMedCentral
16.
Andersen SL. Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev. 2003;27(1–2):3–18.CrossRefPubMed
17.
Hu J, Vacas S, Feng X, Lutrin D, Uchida Y, Lai IK, Maze M. Dexmedetomidine prevents Cognitive decline by enhancing resolution of high mobility Group Box 1 protein-induced inflammation through a Vagomimetic Action in mice. Anesthesiology. 2018;128(5):921–31.CrossRefPubMed
18.
Othman MZ, Hassan Z, Che Has AT. Morris water maze: a versatile and pertinent tool for assessing spatial learning and memory. Exp Anim. 2022;71(3):264–80.
19.
Li J, Guo M, Liu Y, Wu G, Miao L, Zhang J, Zuo Z, Li Y. Both GSK-3beta/CRMP2 and CDK5/CRMP2 pathways participate in the protection of dexmedetomidine against propofol-induced learning and memory impairment in neonatal rats. Toxicol Sci. 2019 Jun 10:kfz135.
20.
Mathiasen JR, DiCamillo A. Novel object recognition in the rat: a facile assay for cognitive function. Curr Protoc Pharmacol 2010, Chap. 5:Unit 5 59.
21.
Zheng T, Zheng C, Gao F, Huang F, Hu B, Zheng X. Dexmedetomidine suppresses bupivacaine-induced parthanatos in human SH-SY5Y cells via the miR-7-5p/PARP1 axis-mediated ROS. Naunyn Schmiedebergs Arch Pharmacol. 2021;394(4):783–96.CrossRefPubMed
22.
O’Toole JF, Patel HV, Naples CJ, Fujioka H, Hoppel CL. Decreased cytochrome c mediates an age-related decline of oxidative phosphorylation in rat kidney mitochondria. Biochem J. 2010;427(1):105–12.CrossRefPubMed
23.
Liu Y, Yu S, Xing X, Qiao J, Yin Y, Wang J, Liu M, Zhang W. Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex.Mol Med Rep2021, 24(6).
24.
Norden DM, Trojanowski PJ, Villanueva E, Navarro E, Godbout JP. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia. 2016;64(2):300–16.CrossRefPubMed
25.
Xiong B, Shi Q, Fang H. Dexmedetomidine alleviates postoperative cognitive dysfunction by inhibiting neuron excitation in aged rats. Am J Transl Res. 2016;8(1):70–80.PubMedPubMedCentral
26.
27.
Johnson JA, Ogbi M. Targeting the F1Fo ATP synthase: modulation of the body’s powerhouse and its implications for human disease. Curr Med Chem. 2011;18(30):4684–714.CrossRefPubMed
28.
Li J, Zhu X, Yang S, Xu H, Guo M, Yao Y, Huang Z, Lin D. Lidocaine attenuates cognitive impairment after isoflurane anesthesia by reducing mitochondrial damage. Neurochem Res. 2019;44(7):1703–14.CrossRefPubMed
29.
Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med. 2008;14(2):45–53.CrossRefPubMedPubMedCentral
30.
Chen Y, Zhang P, Lin X, Zhang H, Miao J, Zhou Y, Chen G. Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats. Aging (Albany NY). 2020;12(17):17235–56.
31.
Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI, Solaini G. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging. 2002;23(3):371–6.CrossRefPubMed
32.
Esparza-Molto PB, Romero-Carraminana I, Nunez de Arenas C, Pereira MP, Blanco N, Pardo B, Bates GR, Sanchez-Castillo C, Artuch R, Murphy MP, et al. Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition. PLoS Biol. 2021;19(5):e3001252.CrossRefPubMedPubMedCentral
33.
Terni B, Boada J, Portero-Otin M, Pamplona R, Ferrer I. Mitochondrial ATP-synthase in the entorhinal cortex is a target of oxidative stress at stages I/II of Alzheimer’s disease pathology. Brain Pathol. 2010;20(1):222–33.CrossRefPubMed
34.
Li Y, Wen S, Li D, Xie J, Wei X, Li X, Liu Y, Fang H, Yang Y, Lyu J. SURF1 mutations in chinese patients with Leigh syndrome: novel mutations, mutation spectrum, and the functional consequences. Gene. 2018;674:15–24.CrossRefPubMed
35.
Cadonic C, Sabbir MG, Albensi BC. Mechanisms of mitochondrial dysfunction in Alzheimer’s Disease. Mol Neurobiol. 2016;53(9):6078–90.CrossRefPubMed
36.
Chandrasekaran K, Hatanpaa K, Brady DR, Stoll J, Rapoport SI. Downregulation of oxidative phosphorylation in Alzheimer disease: loss of cytochrome oxidase subunit mRNA in the hippocampus and entorhinal cortex. Brain Res. 1998;796(1–2):13–9.CrossRefPubMed
37.
Douiev L, Abu-Libdeh B, Saada A. Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA damage. Eur J Hum Genet. 2018;26(4):579–81.CrossRefPubMedPubMedCentral
38.
Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, Ganie SA. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother. 2015;74:101–10.CrossRefPubMed
39.
Giridharan VV, Collodel A, Generoso JS, Scaini G, Wassather R, Selvaraj S, Hasbun R, Dal-Pizzol F, Petronilho F, Barichello T. Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo PET study. J Neuroinflammation. 2020;17(1):5.CrossRefPubMedPubMedCentral
40.
Ghosh C, Mukherjee S, Dey SG. Direct electron transfer between Cyt c and heme-abeta relevant to Alzheimer’s disease. Chem Commun (Camb). 2013;49(51):5754–6.CrossRefPubMed
41.
Gouveia A, Bajwa E, Klegeris A. Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions. Biochim Biophys Acta Gen Subj. 2017;1861(9):2274–81.CrossRefPubMed
42.
Hu Z, Yu F, Gong P, Qiu Y, Zhou W, Cui Y, Li J, Chen H. Subneurotoxic copper(II)-induced NF-kappaB-dependent microglial activation is associated with mitochondrial ROS. Toxicol Appl Pharmacol. 2014;276(2):95–103.CrossRefPubMed
43.
Bader V, Winklhofer KF. Mitochondria at the interface between neurodegeneration and neuroinflammation. Semin Cell Dev Biol. 2020;99:163–71.CrossRefPubMed
Metadata
Title
Dexmedetomidine attenuates postoperative spatial memory impairment after surgery by reducing cytochrome C
Authors
Lina Sun
Kun Niu
Jian Guo
Jingru Tu
Baofeng Ma
Jianxiong An
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Anesthesiology / Issue 1/2023
Electronic ISSN: 1471-2253
DOI
https://doi.org/10.1186/s12871-023-02035-x

Other articles of this Issue 1/2023

BMC Anesthesiology 1/2023 Go to the issue

Research

Impact of patent foramen ovale on short-term outcomes in children with biliary atresia undergoing living donor liver transplantation: a retrospective cohort study

Correction

Correction: Effect of individualized treatment strategy on postoperative nausea and vomiting in gynaecological laparoscopic surgery: a double‑blind, randomized, controlled trial

Research

Correlation between mortality and blood transfusion in patients with major surgery initially admitted to intensive care unit: a retrospective analysis

Research

Efficacy and safety of remimazolam compared with propofol in hypertensive patients undergoing breast cancer surgery: a single-center, randomized, controlled study

Research

Role of platelet to albumin ratio for predicting persistent acute kidney injury in patients admitted to the intensive care unit

Research

A method for calculating left ventricular end-diastolic volume as an index of left ventricular preload from the pre-ejection period, ejection time, blood pressure, and stroke volume: a prospective, observational study