[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content
Springer Nature Link
Log in

Dexmedetomidine alleviates sevoflurane-induced neurotoxicity via mitophagy signaling

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Dexmedetomidine, a class of α2-adrenergic agonist, was reported to exert a neuroprotective effect on sevoflurane-induced neurotoxicity. However, the specific mechanisms have not been fully clarified yet. The aim of our study is to uncover the role of dexmedetomidine in sevoflurane-induced neurotoxicity. The rats pretreated with dexmedetomidine and/or Rapamycin 3-Methyladenine were housed in a box containing 30% O2, 68% N2 and 2% sevoflurane for 4 h for anesthesia. 24 h after drug injection, Morris water maze test was used to evaluate rats’ learning and memory ability. Hematoxylin & eosin (H&E) staining was adopted to analyze the pathological changes of hippocampus. TUNEL assay was performed to measure cell apoptosis in hippocampus. Immunofluorescent assay was utilized to detect HSP60 level. The protein levels of LC3I, LC3II, Beclin-1, CypD, VDAC1 and Tom20 were examined by western blot. 5 weeks after drug injection, Morris water maze test was used to evaluate rats’ learning and memory ability again. Dexmedetomidine alleviated sevoflurane-induced nerve injury and the impairment of learning and memory abilities. Additionally, dexmedetomidine inhibited sevoflurane-induced cell apoptosis in hippocampus. In mechanism, dexmedetomidine activated mitophagy to mitigate neurotoxicity by enhancing LC3II/LC3I ratio, HSP60, Beclin-1, CypD, VDAC1 and Tom20 protein levels in hippocampus. Dexmedetomidine alleviates sevoflurane-induced neurotoxicity via mitophagy signaling, offering a potential strategy for sevoflurane-induced neurotoxicity treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

Con + NS + DMSO:

Control + normal saline + DMSO

Sev + NS + DMSO:

Sevoflurane + normal saline + DMSO

Sev + Dex + DMSO:

Sevoflurane + dexmedetomidine + DMSO

Sev + NS + Rapam:

Sevoflurane + rapamycin + normal saline

Sev + dex + 3-MA:

Sevoflurane + dexmedetomidine + 3-Methyladenine

PVDF:

Polyvinylidene fluoride

PBS:

Phosphate buffer saline

MWM:

Morris water maze

IF:

Immunofluorescent

CSU:

Confocal scanner unit

CypD:

Cyclophilin D

TUNEL:

Terminal deoxynucleotidyltransferase dUTP nick end labeling

H&E:

Hematoxylin & eosin

References

  1. Amorim MA, Goveia CS, Magalhaes E, Ladeira LC, Moreira LG, Miranda DB (2017) Effect of dexmedetomidine in children undergoing general anesthesia with sevoflurane: a meta-analysis. Braz J Anesthesiol 67(2):193–198. https://doi.org/10.1016/j.bjane.2016.02.007

    Article  PubMed  Google Scholar 

  2. Ramos Ramos V, Mesa Suarez P, Santotoribio JD, Gonzalez Garcia MA, Munoz Hoyos A (2017) Neuroprotective effect of sevoflurane in general anaesthesia. Med Clin 148(4):158–160. https://doi.org/10.1016/j.medcli.2016.10.039

    Article  Google Scholar 

  3. Oliveira M, Fernandes AL, Vargas S (2018) Using sevoflurane in a pediatric patient with nemaline rod myopathy. Paediatr Anaesth 28(8):749–750. https://doi.org/10.1111/pan.13458

    Article  PubMed  Google Scholar 

  4. Rigouzzo A, Khoy-Ear L, Laude D, Louvet N, Moutard ML, Sabourdin N, Constant I (2019) EEG profiles during general anesthesia in children: a comparative study between sevoflurane and propofol. Paediatr Anaesth 29(3):250–257. https://doi.org/10.1111/pan.13579

    Article  PubMed  Google Scholar 

  5. Liu B, Ou G, Chen Y, Zhang J (2019) Inhibition of protein tyrosine phosphatase 1B protects against sevoflurane-induced neurotoxicity mediated by ER stress in developing brain. Brain Res Bull 146:28–39. https://doi.org/10.1016/j.brainresbull.2018.12.006

    Article  CAS  PubMed  Google Scholar 

  6. Keating GM (2015) Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs 75(10):1119–1130. https://doi.org/10.1007/s40265-015-0419-5

    Article  CAS  PubMed  Google Scholar 

  7. Shan Y, Yang F, Tang Z, Bi C, Sun S, Zhang Y, Liu H (2018) Dexmedetomidine ameliorates the neurotoxicity of sevoflurane on the immature brain through the BMP/SMAD signaling pathway. Front Neurosci 12:964. https://doi.org/10.3389/fnins.2018.00964

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sottas CE, Anderson BJ (2017) Dexmedetomidine: the new all-in-one drug in paediatric anaesthesia? Curr Opin Anaesthesiol 30(4):441–451. https://doi.org/10.1097/aco.0000000000000488

    Article  CAS  PubMed  Google Scholar 

  9. Perez-Zoghbi JF, Zhu W, Grafe MR, Brambrink AM (2017) Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. Br J Anaesth 119(3):506–516. https://doi.org/10.1093/bja/aex222

    Article  CAS  PubMed  Google Scholar 

  10. Wang N, Wang M (2019) Dexmedetomidine suppresses sevoflurane anesthesia-induced neuroinflammation through activation of the PI3K/Akt/mTOR pathway. BMC Anesthesiol 19(1):134. https://doi.org/10.1186/s12871-019-0808-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Parzych KR, Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20(3):460–473. https://doi.org/10.1089/ars.2013.5371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Scrivo A, Bourdenx M, Pampliega O, Cuervo AM (2018) Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurol 17(9):802–815. https://doi.org/10.1016/s1474-4422(18)30238-2

    Article  PubMed  PubMed Central  Google Scholar 

  13. Casarejos MJ, Solano RM, Rodriguez-Navarro JA, Gomez A, Perucho J, Castano JG, Garcia de Yebenes J, Mena MA (2009) Parkin deficiency increases the resistance of midbrain neurons and glia to mild proteasome inhibition: the role of autophagy and glutathione homeostasis. J Neurochem 110(5):1523–1537. https://doi.org/10.1111/j.1471-4159.2009.06248.x

    Article  CAS  PubMed  Google Scholar 

  14. Ramkumar A, Murthy D, Raja DA, Singh A, Krishnan A, Khanna S, Vats A, Thukral L, Sharma P, Sivasubbu S, Rani R, Natarajan VT, Gokhale RS (2017) Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal tracks. Autophagy 13(8):1331–1347. https://doi.org/10.1080/15548627.2017.1327509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chmielewska M, Skibinska I, Kotwicka M (2017) Mitochondria: target organelles for estrogen action. Postepy higieny i medycyny doswiadczalnej 71(0):454–465. https://doi.org/10.5604/01.3001.0010.3828

    Article  PubMed  Google Scholar 

  16. Evans A, Neuman N (2016) The mighty mitochondria. Mol Cell 61(5):641. https://doi.org/10.1016/j.molcel.2016.02.002

    Article  CAS  PubMed  Google Scholar 

  17. Kurz FT, Aon MA, O’Rourke B, Armoundas AA (2018) Assessing spatiotemporal and functional organization of mitochondrial networks. Methods Mol Biol 1782:383–402. https://doi.org/10.1007/978-1-4939-7831-1_23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shiba-Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, Hattori N (2012) PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep 2:1002. https://doi.org/10.1038/srep01002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sauve V, Sung G, Soya N, Kozlov G, Blaimschein N, Miotto LS, Trempe JF, Lukacs GL, Gehring K (2018) Mechanism of parkin activation by phosphorylation. Nat Struct Mol Biol 25(7):623–630. https://doi.org/10.1038/s41594-018-0088-7

    Article  CAS  PubMed  Google Scholar 

  20. Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 205(2):143–153. https://doi.org/10.1083/jcb.201402104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Okatsu K, Koyano F, Kimura M, Kosako H, Saeki Y, Tanaka K, Matsuda N (2015) Phosphorylated ubiquitin chain is the genuine Parkin receptor. J Cell Biol 209(1):111–128. https://doi.org/10.1083/jcb.201410050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ordureau A, Heo JM, Duda DM, Paulo JA, Olszewski JL, Yanishevski D, Rinehart J, Schulman BA, Harper JW (2015) Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci USA 112(21):6637–6642. https://doi.org/10.1073/pnas.1506593112

    Article  CAS  PubMed  Google Scholar 

  23. Xiao B, Deng X, Lim GGY, Xie S, Zhou ZD, Lim KL, Tan EK (2017) Superoxide drives progression of Parkin/PINK1-dependent mitophagy following translocation of Parkin to mitochondria. Cell Death Dis 8(10):e3097. https://doi.org/10.1038/cddis.2017.463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zheng Q, Li Z, Zhou S, Zhang Q, Zhou L, Fu X, Yang L, Ma Y, Hao X (2017) Heparin-binding hemagglutinin of mycobacterium tuberculosis is an inhibitor of autophagy. Front Cell Infect Microbiol 7:33. https://doi.org/10.3389/fcimb.2017.00033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shan Y, Sun S, Yang F, Shang N, Liu H (2018) Dexmedetomidine protects the developing rat brain against the neurotoxicity wrought by sevoflurane: role of autophagy and Drp1-Bax signaling. Drug Des Dev Ther 12:3617–3624. https://doi.org/10.2147/dddt.S180343

    Article  CAS  Google Scholar 

  26. Wang X, Deng Q, Liu B, Yu X (2017) Preventing emergence agitation using ancillary drugs with sevoflurane for pediatric anesthesia: a network meta-analysis. Mol Neurobiol 54(9):7312–7326. https://doi.org/10.1007/s12035-016-0229-0

    Article  CAS  PubMed  Google Scholar 

  27. Cornelissen L, Kim SE, Purdon PL, Brown EN, Berde CB (2015) Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants. eLife 4:e06513. https://doi.org/10.7554/eLife.06513

    Article  PubMed  PubMed Central  Google Scholar 

  28. Amorim MA, Goveia CS, Magalhaes E, Ladeira LC, Moreira LG, de Miranda DB (2017) Effect of dexmedetomidine in children undergoing general anesthesia with sevoflurane: a meta-analysis. Revista Brasileira Anestesiol 67(2):193–198. https://doi.org/10.1016/j.bjan.2016.02.015

    Article  Google Scholar 

  29. Haas DA (2011) Alternative mandibular nerve block techniques: a review of the Gow-Gates and Akinosi-Vazirani closed-mouth mandibular nerve block techniques. J Am Dent Assoc 142(Suppl 3):8s–12s. https://doi.org/10.14219/jada.archive.2011.0341

    Article  PubMed  Google Scholar 

  30. Li Y, Zeng M, Chen W, Liu C, Wang F, Han X, Zuo Z, Peng S (2014) Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats. PLoS ONE 9(4):e93639. https://doi.org/10.1371/journal.pone.0093639

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wang DS, Kaneshwaran K, Lei G, Mostafa F, Wang J, Lecker I, Avramescu S, Xie YF, Chan NK, Fernandez-Escobar A, Woo J, Chan D, Ramsey AJ, Sivak JM, Lee CJ, Bonin RP, Orser BA (2018) Dexmedetomidine prevents excessive gamma-aminobutyric acid type A receptor function after anesthesia. Anesthesiology 129(3):477–489. https://doi.org/10.1097/aln.0000000000002311

    Article  CAS  PubMed  Google Scholar 

  32. Bo LJ, Yu PX, Zhang FZ, Dong ZM (2018) Dexmedetomidine mitigates sevoflurane-induced cell cycle arrest in hippocampus. J Anesthes 32(5):717–724. https://doi.org/10.1007/s00540-018-2545-1

    Article  Google Scholar 

  33. Meng L, Li L, Lu S, Li K, Su Z, Wang Y, Fan X, Li X, Zhao G (2018) The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-kappaB and PI3K/Akt/mTOR pathways. Mol Immunol 94:7–17. https://doi.org/10.1016/j.molimm.2017.12.008

    Article  CAS  PubMed  Google Scholar 

  34. Tu Y, Liang Y, Xiao Y, Lv J, Guan R, Xiao F, Xie Y, Xiao Q (2019) Dexmedetomidine attenuates the neurotoxicity of propofol toward primary hippocampal neurons in vitro via Erk1/2/CREB/BDNF signaling pathways. Drug Des Devel Ther 13:695–706. https://doi.org/10.2147/dddt.S188436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lv J, Wei Y, Chen Y, Zhang X, Gong Z, Jiang Y, Gong Q, Zhou L, Wang H, Xie Y (2017) Dexmedetomidine attenuates propofol-induce neuroapoptosis partly via the activation of the PI3k/Akt/GSK3beta pathway in the hippocampus of neonatal rats. Environm Toxicol Pharmacol 52:121–128. https://doi.org/10.1016/j.etap.2017.03.017

    Article  CAS  Google Scholar 

  36. Kulkarni A, Chen J, Maday S (2018) Neuronal autophagy and intercellular regulation of homeostasis in the brain. Curr Opin Neurobiol 51:29–36. https://doi.org/10.1016/j.conb.2018.02.008

    Article  CAS  PubMed  Google Scholar 

  37. Wang X, Dong Y, Zhang Y, Li T, Xie Z (2019) Sevoflurane induces cognitive impairment in young mice via autophagy. PLoS ONE 14(5):e0216372. https://doi.org/10.1371/journal.pone.0216372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fan L, Chen D, Wang J, Wu Y, Li D, Yu X (2017) Sevoflurane ameliorates myocardial cell injury by inducing autophagy via the deacetylation of LC3 by SIRT1. Anal Cell Pathol 2017:6281285. https://doi.org/10.1155/2017/6281285

    Article  CAS  Google Scholar 

  39. Zhao Y, Feng X, Li B, Sha J, Wang C, Yang T, Cui H, Fan H (2020) Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. Front Pharmacol 11:128. https://doi.org/10.3389/fphar.2020.00128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research did not receive any specific Grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, No. 44 Xiaoheyan road, Dadong district, Shenyang, 110042, Liaoning, China

    Liangyuan Suo & Mingyu Wang

Authors
  1. Liangyuan Suo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LYS: Investigation, Methodology, Writing-review & editing; MYW: Supervision, Writing-original draft. Review & editing. All authors read and approved the final manuscript.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Ethical approval

All animal operations were approved by the ethic committee of Animal Experiment Center of the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suo, L., Wang, M. Dexmedetomidine alleviates sevoflurane-induced neurotoxicity via mitophagy signaling . Mol Biol Rep 47, 7893–7901 (2020). https://doi.org/10.1007/s11033-020-05868-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05868-8

Keywords

Search

Navigation