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Journal of Anesthesia

, Volume 32, Issue 5, pp 717–724 | Cite as

Dexmedetomidine mitigates sevoflurane-induced cell cycle arrest in hippocampus

  • Li-Jun Bo
  • Pei-Xia Yu
  • Fu-Zhen Zhang
  • Zhen-Ming Dong
Original Article
  • 169 Downloads

Abstract

Background

Epidemiologic studies suggest the possibility of a modestly elevated risk of adverse neurodevelopmental outcomes in children exposed to anesthesia during early childhood. Sevoflurane is widely used in pediatric anesthetic practice because of its rapid induction and lower pungency. However, it is reported that sevoflurane leads to the long-term cognitive impairment. Some evidence revealed that the selective α2-adrenoreceptor agonist dexmedetomidine (DEX) exerts neuroprotective effects in various brain injury models of animals. But the role of DEX on sevoflurane-induced neuro-damage remains elusive.

Materials and methods

In our study, we isolated the hippocampal neuron cells from newborn neonatal rats and verified the purity of neurons by immunocytochemistry. We employed the flow cytometry and western blot to examine the effect of sevoflurane, DEX and α2-adrenergic receptor antagonist yohimbine on cell cycle distribution.

Results

Immunocytochemistry results showed the purity of neurons > 94%, which provided a good model for neural pharmacology experiments. The exposure of sevoflurane-induced cell cycle arrest at S phase and suppressed the expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB). The addition of DEX suppressed sevoflurane-induced cell cycle arrest and the inhibitory of BDNF and TrkB expression. But the function of DEX was partly blocked by a α2 adrenergic receptor blocker yohimbine.

Conclusion

Sevoflurane suppressed neuron cell proliferation via inhibiting the expression of BDNF and TrkB, and DEX relieved the neurotoxicity induced by sevoflurane via α2 adrenergic receptor. These findings provided new evidence that DEX exerted as a neuroprotective strategy in sevoflurane-induced neuro-damage, and provided new basis for the clinical application of DEX.

Keywords

Anesthetics Sevoflurane Neuroprotection Dexmedetomidine Brain-derived neurotrophic factor-tyrosine kinase B 

Abbreviations

DEX

Dexmedetomidine

MAP-2

Microtubule-associated protein 2

BDNF

Brain-derived neurotrophic factor

TrkB

Tyrosine kinase B

MAC

Minimum alveolar concentration

GFAP

Glial fibrillary acidic protein

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Ma R, Wang X, Peng P, Xiong J, Dong H, Wang L, Ding Z. Alpha-lipoic acid inhibits sevoflurane-induced neuronal apoptosis through PI3K/Akt signalling pathway. Cell Biochem Funct. 2016;34:42–7.CrossRefGoogle Scholar
  2. 2.
    Andropoulos DB. Effect of Anesthesia on the Developing Brain: Infant and Fetus. Fetal Diagn Ther. 2018;43:1–11.CrossRefGoogle Scholar
  3. 3.
    Poor Zamany Nejat Kermany M, Roodneshin F, Ahmadi Dizgah N, Gerami E, Riahi E. Early childhood exposure to short periods of sevoflurane is not associated with later, lasting cognitive deficits. Paediatr Anaesth. 2016;26:1018–25.CrossRefGoogle Scholar
  4. 4.
    Costi D, Cyna AM, Ahmed S, Stephens K, Strickland P, Ellwood J, Larsson JN, Chooi C, Burgoyne LL, Middleton P. Effects of sevoflurane versus other general anaesthesia on emergence agitation in children. Cochrane Database Syst Rev. 2014;2014:CD007084.Google Scholar
  5. 5.
    Jeon YT, Hwang JW, Lim YJ, Park SK, Park HP. Postischemic sevoflurane offers no additional neuroprotective benefit to preischemic dexmedetomidine. J Neurosurg Anesthesiol. 2013;25:184–90.CrossRefGoogle Scholar
  6. 6.
    Liu Y, Lin D, Liu C, Zhao Y, Shen Z, Zhang K, Cao M, Li Y. Cyclin-dependent kinase 5/collapsin response mediator protein 2 pathway may mediate sevoflurane-induced dendritic development abnormalities in rat cortical neurons. Neurosci Lett. 2017;651:21–9.CrossRefGoogle Scholar
  7. 7.
    Liang G, Ward C, Peng J, Zhao Y, Huang B, Wei H. Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology. 2010;112:1325–34.CrossRefGoogle Scholar
  8. 8.
    Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 2009;110:628–37.CrossRefGoogle Scholar
  9. 9.
    Sun LS, Li G, Dimaggio C, Byrne M, Rauh V, Brooks-Gunn J, Kakavouli A, Wood A. Anesthesia and neurodevelopment in children: time for an answer? Anesthesiology. 2008;109:757–61.CrossRefGoogle Scholar
  10. 10.
    Wang Q, Tan Y, Zhang N, Xu Y, Wei W, She Y, Bi X, Zhao B, Ruan X. Dexmedetomidine inhibits activation of the MAPK pathway and protects PC12 and NG108-15 cells from lidocaine-induced cytotoxicity at its maximum safe dose. Biomed Pharmacother. 2017;91:162–6.CrossRefGoogle Scholar
  11. 11.
    Wang X, Zhao B, Li X. Dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat. Int J Clin Exp Med. 2015;8:17281–8.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Sanders RD, Xu J, Shu Y, Januszewski A, Halder S, Fidalgo A, Sun P, Hossain M, Ma D, Maze M. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology. 2009;110:1077–85.CrossRefGoogle Scholar
  13. 13.
    Sanders RD, Sun P, Patel S, Li M, Maze M, Ma D. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand. 2010;54:710–6.CrossRefGoogle Scholar
  14. 14.
    Li Y, Zeng M, Chen W, Liu C, Wang F, Han X, Zuo Z, Peng S. Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats. PLoS One. 2014;9:e93639.CrossRefGoogle Scholar
  15. 15.
    Luo L, Liu XL, Li J, Mu RH, Liu Q, Yi LT, Geng D. Macranthol promotes hippocampal neuronal proliferation in mice via BDNF-TrkB-PI3K/Akt signaling pathway. Eur J Pharmacol. 2015;762:357–63.CrossRefGoogle Scholar
  16. 16.
    Schoeler M, Loetscher PD, Rossaint R, Fahlenkamp AV, Eberhardt G, Rex S, Weis J, Coburn M. Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. BMC Neurol. 2012;12:20.CrossRefGoogle Scholar
  17. 17.
    Lv J, Ou W, Zou XH, Yao Y, Wu JL. Effect of dexmedetomidine on hippocampal neuron development and BDNF-TrkB signal expression in neonatal rats. Neuropsychiatr Dis Treat. 2016;12:3153–9.CrossRefGoogle Scholar
  18. 18.
    Lu P, Jones LL, Snyder EY, Tuszynski MH. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol. 2003;181:115–29.CrossRefGoogle Scholar
  19. 19.
    Whitaker EE, Zheng CZ, Bissonnette B, Miller AD, Koppert TL, Tobias JD, Pierson CR, Christofi FL. Use of a piglet model for the study of anesthetic-induced developmental neurotoxicity (AIDN): a translational neuroscience approach. J Vis Exp. 2017;124:1–12.Google Scholar
  20. 20.
    Kim EH, Song IK, Lee JH, Kim HS, Kim HC, Yoon SH, Jang YE, Kim JT. Desflurane versus sevoflurane in pediatric anesthesia with a laryngeal mask airway: a randomized controlled trial. Medicine (Baltimore). 2017;96:e7977.CrossRefGoogle Scholar
  21. 21.
    Spera AL, Saxen MA, Yepes JF, Jones JE, Sanders BJ. Office-based anesthesia: safety and outcomes in pediatric dental patients. Anesth Prog. 2017;64:144–52.CrossRefGoogle Scholar
  22. 22.
    Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, Stargatt R, Bellinger DC, Schuster T, Arnup SJ, Hardy P, Hunt RW, Takagi MJ, Giribaldi G, Hartmann PL, Salvo I, Morton NS, von Ungern Sternberg BS, Locatelli BG, Wilton N, Lynn A, Thomas JJ, Polaner D, Bagshaw O, Szmuk P, Absalom AR, Frawley G, Berde C, Ormond GD, Marmor J, McCann ME. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016;387:239–50.CrossRefGoogle Scholar
  23. 23.
    Jia M, Liu WX, Yang JJ, Xu N, Xie ZM, Ju LS, Ji MH, Martynyuk AE. Role of histone acetylation in long-term neurobehavioral effects of neonatal exposure to sevoflurane in rats. Neurobiol Dis. 2016;91:209–20.CrossRefGoogle Scholar
  24. 24.
    Nie H, Peng Z, Lao N, Dong H, Xiong L. Effects of sevoflurane on self-renewal capacity and differentiation of cultured neural stem cells. Neurochem Res. 2013;38:1758–67.CrossRefGoogle Scholar
  25. 25.
    Lu Y, Huang Y, Jiang J, Hu R, Yang Y, Jiang H, Yan J. Neuronal apoptosis may not contribute to the long-term cognitive dysfunction induced by a brief exposure to 2% sevoflurane in developing rats. Biomed Pharmacother. 2016;78:322–8.CrossRefGoogle Scholar
  26. 26.
    Rong H, Zhao Z, Feng J, Lei Y, Wu H, Sun R, Zhang Z, Hou B, Zhang W, Sun Y, Gu X, Ma Z, Liu Y. The effects of dexmedetomidine pretreatment on the pro- and anti-inflammation systems after spinal cord injury in rats. Brain Behav Immun. 2017;64:195–207.CrossRefGoogle Scholar
  27. 27.
    Chen H, Sun X, Yang X, Hou Y, Yu X, Wang Y, Wu J, Liu D, Wang H, Yu J, Yi W. Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor (NF)-kappaB signaling pathway. Bosn J Basic Med Sci. 2018;18:162–9.Google Scholar
  28. 28.
    Chen G, Le Y, Zhou L, Gong L, Li X, Li Y, Liao Q, Duan K, Tong J, Ouyang W. Dexmedetomidine inhibits maturation and function of human cord blood-derived dendritic cells by interfering with synthesis and secretion of IL-12 and IL-23. PLoS One. 2016;11:e0153288.CrossRefGoogle Scholar
  29. 29.
    Dahmani S, Paris A, Jannier V, Hein L, Rouelle D, Scholz J, Gressens P, Mantz J. Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinase 1 and 2 content by an alpha 2-adrenoceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors. Anesthesiology. 2008;108:457–66.CrossRefGoogle Scholar
  30. 30.
    Zhang H, Yan X, Wang DG, Leng YF, Wan ZH, Liu YQ, Zhang Y. Dexmedetomidine relieves formaldehyde-induced pain in rats through both alpha2 adrenoceptor and imidazoline receptor. Biomed Pharmacother. 2017;90:914–20.CrossRefGoogle Scholar
  31. 31.
    Hoppe JB, Coradini K, Frozza RL, Oliveira CM, Meneghetti AB, Bernardi A, Pires ES, Beck RC, Salbego CG. Free and nanoencapsulated curcumin suppress beta-amyloid-induced cognitive impairments in rats: involvement of BDNF and Akt/GSK-3beta signaling pathway. Neurobiol Learn Mem. 2013;106:134–44.CrossRefGoogle Scholar
  32. 32.
    Liu XS, Xue QS, Zeng QW, Li Q, Liu J, Feng XM, Yu BW. Sevoflurane impairs memory consolidation in rats, possibly through inhibiting phosphorylation of glycogen synthase kinase-3beta in the hippocampus. Neurobiol Learn Mem. 2010;94:461–7.CrossRefGoogle Scholar
  33. 33.
    Baquet ZC, Gorski JA, Jones KR. Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J Neurosci. 2004;24:4250–8.CrossRefGoogle Scholar
  34. 34.
    Cheng A, Wang S, Yang D, Xiao R, Mattson MP. Calmodulin mediates brain-derived neurotrophic factor cell survival signaling upstream of Akt kinase in embryonic neocortical neurons. J Biol Chem. 2003;278:7591–9.CrossRefGoogle Scholar
  35. 35.
    Wang JY, Feng Y, Fu YH, Liu GL. Effect of sevoflurane anesthesia on brain is mediated by lncRNA HOTAIR. J Mol Neurosci. 2018;64:346–51.CrossRefGoogle Scholar
  36. 36.
    Ding ML, Ma H, Man YG, Lv HY. Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can J Physiol Pharmacol. 2017;95:1396–405.CrossRefGoogle Scholar
  37. 37.
    Ozer AB, Ceribasi S, Ceribasi AO, Demirel I, Bayar MK, Ustundag B, Ileri A, Erhan OL. Effects of sevoflurane on apoptosis, BDNF and cognitive functions in neonatal rats. Bratisl Lek Listy. 2017;118:80–4.PubMedGoogle Scholar
  38. 38.
    Han XD, Li M, Zhang XG, Xue ZG, Cang J. Single sevoflurane exposure increases methyl-CpG island binding protein 2 phosphorylation in the hippocampus of developing mice. Mol Med Rep. 2015;11:226–30.CrossRefGoogle Scholar
  39. 39.
    Bretin S, Reibel S, Charrier E, Maus-Moatti M, Auvergnon N, Thevenoux A, Glowinski J, Rogemond V, Premont J, Honnorat J, Gauchy C. Differential expression of CRMP1, CRMP2A, CRMP2B, and CRMP5 in axons or dendrites of distinct neurons in the mouse brain. J Comp Neurol. 2005;486:1–17.CrossRefGoogle Scholar
  40. 40.
    Liu Y, Liu C, Zeng M, Han X, Zhang K, Fu Y, Li J, Li Y. Influence of sevoflurane exposure on mitogen-activated protein kinases and Akt/GSK-3beta/CRMP-2 signaling pathways in the developing rat brain. Exp Ther Med. 2018;15:2066–73.PubMedGoogle Scholar
  41. 41.
    Kumamaru E, Numakawa T, Adachi N, Kunugi H. Glucocorticoid suppresses BDNF-stimulated MAPK/ERK pathway via inhibiting interaction of Shp2 with TrkB. FEBS Lett. 2011;585:3224–8.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2018

Authors and Affiliations

  • Li-Jun Bo
    • 1
  • Pei-Xia Yu
    • 2
  • Fu-Zhen Zhang
    • 1
  • Zhen-Ming Dong
    • 1
  1. 1.Department of AnesthesiologyThe Second Hospital of Hebei Medical UniversityShijiazhuangChina
  2. 2.Department of AnesthesiologyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina

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