Data from animal experiments suggest that exposure to general anesthetics in early life inhibits neurogenesis and causes long-term memory deficit. Considering short operating times and the popularity of sevoflurane in pediatric anesthesia, it is important to verify the effects of short-period exposure to sevoflurane on the developing brain.
We measured the effects of short-term exposure (2 h) to 3%, 6%, or 8% sevoflurane, the most commonly used anesthetic, on neural precursor cells derived from human embryonic stem cells, SNUhES32. Cell survival, proliferation, apoptosis, and differentiation on days 1, 3, 5, and 7 post treatment were analyzed.
Treatment with 6% sevoflurane increased cell viability (P = 0.046) and decreased apoptosis (P = 0.014) on day 5, but the effect did not persist on day 7. Survival and apoptosis were not affected by 3% and 8% sevoflurane; there was no effect of proliferation at any of the tested concentrations. The differentiation of cells exposed to 6% or 8% sevoflurane decreased on day 1 (P = 0.033 and P = 0.036 for 6% and 8% sevoflurane, respectively) but was again normalized on days 3–7.
Clinically relevant treatment with sevoflurane for 2 h induces no significant changes in the survival, proliferation, apoptosis, and differentiation of human neural precursor cells, although supraclinical doses of sevoflurane do alter human neurogenesis transiently.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Loepke AW, Istaphanous GK, McAuliffe JJ 3rd, Miles L, Hughes EA, McCann JC, Harlow KE, Kurth CD, Williams MT, Vorhees CV, Danzer SC. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg. 2009;108:90–104.
Fang F, Xue Z, Cang J. Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function. Neurosci Bull. 2012;28:499–508.
Fujimoto S, Ishikawa M, Nagano M, Sakamoto A. Influence of neonatal sevoflurane exposure on nerve development-related microRNAs and behavior of rats. Biomed Res. 2015;36:347–55.
Zheng H, Dong Y, Xu Z, Crosby G, Culley DJ, Zhang Y, Xie Z. Sevoflurane anesthesia in pregnant mice induces neurotoxicity in fetal and offspring mice. Anesthesiology. 2013;118:516–26.
Kodama M, Satoh Y, Otsubo Y, Araki Y, Yonamine R, Masui K, Kazama T. Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory. Anesthesiology. 2011;115:979–91.
Wang SQ, Fang F, Xue ZG, Cang J, Zhang XG. Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss. Eur Rev Med Pharmacol Sci. 2013;17:941–50.
Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth. 2010;105(suppl 1):i61–8.
DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21:286–91.
Kalkman CJ, Peelen L, Moons KG, Veenhuizen M, Bruens M, Sinnema G, de Jong TP. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009;110:805–12.
Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110:796–804.
Brokhman I, Gamarnik-Ziegler L, Pomp O, Aharonowiz M, Reubinoff BE, Goldstein RS. Peripheral sensory neurons differentiate from neural precursors derived from human embryonic stem cells. Differ Res Biol Divers. 2008;76:145–55.
Johnson MA, Weick JP, Pearce RA, Zhang SC. Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J Neurosci. 2007;27:3069–77.
Cho MS, Lee Y-E, Kim JY, Chung S, Cho YH, Kim D-S, Kang S-M, Lee H, Kim M-H, Kim J-H, Leem JW, Oh SK, Choi YM, Hwang D-Y, Chang JW, Kim D-W. Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA. 2008;105:3392–7.
Cho MS, Hwang DY, Kim DW. Efficient derivation of functional dopaminergic neurons from human embryonic stem cells on a large scale. Nat Protoc. 2008;3:1888–94.
Zhou Z, Ma D. Anaesthetics-induced neurotoxicity in developing brain: an update on preclinical evidence. Brain Sci. 2014;4:136–49.
Wang C, Liu F, Patterson TA, Paule MG, Slikker W Jr. Utilization of neural stem cell-derived models to study anesthesia-related toxicity and preventative approaches. Mol Neurobiol. 2013;48:302–7.
Lerman J. Sevoflurane in pediatric anesthesia. Anesth Analg. 1995;81:S4–10.
Fingar KR, Stocks C, Weiss AJ, Steiner CA. Most frequent operating room procedures performed in US hospitals, 2003–2012: statistical brief #186. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs, Rockville, MD; 2006. http://www.ncbi.nlm.nih.gov/pubmed/25695123
Skalova S, Svadlakova T, Shaikh Qureshi WM, Dev K, Mokry J. Induced pluripotent stem cells and their use in cardiac and neural regenerative medicine. Int J Mol Sci. 2015;16:4043–67.
Hatch DJ. New inhalation agents in paediatric anaesthesia. Br J Anaesth. 1999;83:42–9.
Lu CC, Tsai CS, Ho ST, Chen WY, Wong CS, Wang JJ, Hu OYP, Lin CY. Pharmacokinetics of sevoflurane uptake into the brain and body. Anaesthesia. 2003;58:951–6.
Zhang Y, Dong Y, Zheng H, Shie V, Wang H, Busscher JJ, Yue Y, Xu Z, Xie Z. Sevoflurane inhibits neurogenesis and the Wnt-catenin signaling pathway in mouse neural progenitor cells. Curr Mol Med. 2013;13:1446–54.
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.
Sinner B, Becke K, Engelhard K. General anaesthetics and the developing brain: an overview. Anaesthesia. 2014;69:1009–22.
Zhang X, Liu S, Newport GD, Paule MG, Callicott R, Thompson J, Liu F, Patterson TA, Berridge MS, Apana SM, Brown CC, Maisha MP, Hanig JP, Slikker W Jr, Wang C. In vivo monitoring of sevoflurane-induced adverse effects in neonatal nonhuman primates using small-animal positron emission tomography. Anesthesiology. 2016;125:133–46.
Xiao H, Liu B, Chen Y, Zhang J. Learning, memory and synaptic plasticity in hippocampus in rats exposed to sevoflurane. Int J Dev Neurosci. 2016;48:38–49.
Wang S, Peretich K, Zhao Y, Liang G, Meng Q, Wei H. Anesthesia-induced neurodegeneration in fetal rat brains. Pediatr Res. 2009;66:435–40.
Sun X, Fang B, Zhao X, Zhang G, Ma H. Preconditioning of mesenchymal stem cells by sevoflurane to improve their therapeutic potential. PLoS One. 2014;9:e90667.
Lucchinetti E, Zeisberger SM, Baruscotti I, Wacker J, Feng J, Zaugg K, Dubey R, Zisch AH, Zaugg M. Stem cell-like human endothelial progenitors show enhanced colony-forming capacity after brief sevoflurane exposure: preconditioning of angiogenic cells by volatile anesthetics. Anesth Analg. 2009;109:1117–26.
Wei H, Liang G, Yang H. Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity. Neurosci Lett. 2007;425:59–62.
Zhao P, Zuo Z. Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats. Anesthesiology. 2004;101:695–703.
Jevtovic-Todorovic V, Boscolo A, Sanchez V, Lunardi N. Anesthesia-induced developmental neurodegeneration: the role of neuronal organelles. Front Neurol. 2012;3:141.
Loepke AW, Soriano SG. An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 2008;106:1681–707.
Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108(suppl 3):511–33.
Sohn HM, Kim HY, Park S, Han SH, Kim JH. Isoflurane decreases proliferation and differentiation, but none of the effects persist in human embryonic stem cell-derived neural progenitor cells. J Anesth. 2017;31:36–43.
Yi X, Cai Y, Zhang N, Wang Q, Li W. Sevoflurane inhibits embryonic stem cell self-renewal and subsequent neural differentiation by modulating the let-7a-Lin28 signaling pathway. Cell Tissue Res. 2016;365:319–30. doi:10.1007/s00441-016-2394-x.
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, Consortium GAS. 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.
Pound P, Bracken MB. Is animal research sufficiently evidence based to be a cornerstone of biomedical research? BMJ. 2014;348:g3387.
Hansen TG. Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children. Paediatr Anaesth. 2015;25:65–72.
LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron. 1995;15:1287–98.
Ryu JR, Hong CJ, Kim JY, Kim EK, Sun W, Yu SW. Control of adult neurogenesis by programmed cell death in the mammalian brain. Mol Brain. 2016;9:43.
Yufune S, Satoh Y, Akai R, Yoshinaga Y, Kobayashi Y, Endo S, Kazama T. Suppression of ERK phosphorylation through oxidative stress is involved in the mechanism underlying sevoflurane-induced toxicity in the developing brain. Sci Rep. 2016;6:21859.
Zhou L, Wang Z, Zhou H, Liu T, Lu F, Wang S, Li J, Peng S, Zuo Z. Neonatal exposure to sevoflurane may not cause learning and memory deficits and behavioral abnormality in the childhood of Cynomolgus monkeys. Sci Rep. 2015;5:11145.
This work was supported by Grant 14-2014-010 from the Seoul National University Bundang Hospital Research Fund, Republic of Korea.
Conflict of interest
No competing interests declared.
About this article
Cite this article
Park, JW., Lim, Ms., JI, S.y. et al. Effects of short-term exposure to sevoflurane on the survival, proliferation, apoptosis, and differentiation of neural precursor cells derived from human embryonic stem cells. J Anesth 31, 821–828 (2017). https://doi.org/10.1007/s00540-017-2408-1
- Anesthetics general
- Human embryonic stem cells