Journal of Molecular Neuroscience

, Volume 68, Issue 2, pp 275–286 | Cite as

Euxanthone Ameliorates Sevoflurane-Induced Neurotoxicity in Neonatal Mice

  • Hui Zhou
  • Song Li
  • Gongming WangEmail author


Sevoflurane is a widely used anesthetic. A series of recent studies have shown that exposure to sevoflurane at an early stage is a risk factor for the development of learning and memory dysfunction. Euxanthone is a xanthone derivative obtained from Polygala caudata. This study was designed to investigate whether euxanthone can confer neuroprotective activities against sevoflurane-induced neurotoxicity and to determine the associated molecular mechanisms. Neonatal Sprague-Dawley (male) rats were exposed to sevoflurane with or without euxanthone treatment. The behavioral data of rats were collected at P41 (the beginning of the adult stage). The hippocampal tissue was obtained following exposure to sevoflurane. The reactive oxygen species (ROS) level in the hippocampal tissue was determined by a commercial kit. The expression of apoptotic markers and inflammatory cytokines was determined by western blot. The mRNA and protein expression of Nrf2 were determined by qRT-PCR and western blot, respectively. The rat in vitro model of neurotoxicity was established using isolated hippocampal neurons. Nrf2 expression was repressed by transfection of siRNA. The cell viability was assessed by the CCK-8 assay. The flow cytometry was performed to measure apoptotic cell death. Our data showed that euxanthone treatment at the neonatal stage protected against sevoflurane-induced neurotoxicity in adult rats. At the molecular level, our findings revealed that the neuroprotective activities of euxanthone were associated with decreased sevoflurane-induced apoptosis cell death and neuroinflammation. More importantly, our results provide the experimental evidence that euxanthone confers neuroprotection by upregulating Nrf2 expression. Euxanthone has a therapeutic potential for clinical prevention of sevoflurane-induced neurotoxicity.


Sevoflurane Neurotoxicity Euxanthone Nrf2 Apoptosis Neuroinflammation 



This study was funded by the National Natural Science Foundation of China No. 30872433.

Compliance with Ethical Standards

All protocols of animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Shandong University. Animals were treated in accordance with the Guide for the Care and Use of Laboratory Animals (8th edition, National Academies Press).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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  1. Bai S, Hu Z, Yang Y, Yin Y, Li W, Wu L, Fang M (2016) Anti-inflammatory and neuroprotective effects of triptolide via the NF-kappaB signaling pathway in a rat MCAO model. Anat Rec (Hoboken) 299(2):256–266CrossRefGoogle Scholar
  2. Chaiprasongsuk A, Lohakul J, Soontrapa K, Sampattavanich S, Akarasereenont P, Panich U (2017) Activation of Nrf2 reduces UVA-mediated MMP-1 upregulation via MAPK/AP-1 signaling cascades: the photoprotective effects of sulforaphane and hispidulin. J Pharmacol Exp Ther 360(3):388–398CrossRefGoogle Scholar
  3. Chen G, Gong M, Yan M, Zhang X (2013) Sevoflurane induces endoplasmic reticulum stress mediated apoptosis in hippocampal neurons of aging rats. PLoS One 8(2):e57870CrossRefGoogle Scholar
  4. Costi D et al (2014) Effects of sevoflurane versus other general anaesthesia on emergence agitation in children. Cochrane Database Syst Rev 9:CD007084Google Scholar
  5. Cui RS, Wang K, Wang ZL (2018) Sevoflurane anesthesia alters cognitive function by activating inflammation and cell death in rats. Exp Ther Med 15(5):4127–4130Google Scholar
  6. DiMaggio C, Sun LS, Li G (2011) Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 113(5):1143–1151CrossRefGoogle Scholar
  7. Ha WY, Wu PK, Kok TW, Leung KW, Mak NK, Yue PYK, Ngai SM, Tsai SN, Wong RNS (2006) Involvement of protein kinase C and E2F-5 in euxanthone-induced neurite differentiation of neuroblastoma. Int J Biochem Cell Biol 38(8):1393–1401CrossRefGoogle Scholar
  8. Han LC, Zhang H, Wang W, Wei YY, Sun XX, Yanagawa Y, Li YQ, Xu LX, Wu SX (2010) The effect of sevoflurane inhalation on gabaergic neurons activation: observation on the GAD67-GFP knock-in mouse. Anat Rec (Hoboken) 293(12):2114–2122CrossRefGoogle Scholar
  9. Huang L, Huang K, Ning H (2017) Hispidulin prevents sevoflurane- induced memory dysfunction in aged rats. Biomed Pharmacother 97:412–422CrossRefGoogle Scholar
  10. Jevtovic-Todorovic V (2012) Developmental synaptogenesis and general anesthesia: a kiss of death? Curr Pharm Des 18(38):6225–6231CrossRefGoogle Scholar
  11. Ji MH, Qiu LL, Yang JJ, Zhang H, Sun XR, Zhu SH, Li WY, Yang JJ (2015) Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice. Neurotoxicology 46:155–164CrossRefGoogle Scholar
  12. Kuete V, Mbaveng AT, Nono ECN, Simo CC, Zeino M, Nkengfack AE, Efferth T (2016) Cytotoxicity of seven naturally occurring phenolic compounds towards multi-factorial drug-resistant cancer cells. Phytomedicine 23(8):856–863CrossRefGoogle Scholar
  13. Li R, Zhang LM, Sun WB (2017) Erythropoietin rescues primary rat cortical neurons from pyroptosis and apoptosis via Erk1/2-Nrf2/Bach1 signal pathway. Brain Res Bull 130:236–244CrossRefGoogle Scholar
  14. Lin LL, Huang F, Chen SB, Yang DJ, Chen SL, Yang JS, Xiao PG (2005) Xanthones from the roots of Polygala caudata and their antioxidation and vasodilatation activities in vitro. Planta Med 71(4):372–375CrossRefGoogle Scholar
  15. Liu Y, Zhuang X, Gou L, Ling X, Tian X, Liu L, Zheng Y, Zhang L, Yin X (2013) Protective effects of nizofenone administration on the cognitive impairments induced by chronic restraint stress in mice. Pharmacol Biochem Behav 103(3):474–480CrossRefGoogle Scholar
  16. Liu K, Gao H, Wang Q, Wang L, Zhang B, Han Z, Chen X, Han M, Gao M (2018a) Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer. Cancer Sci 109(5):1369–1381CrossRefGoogle Scholar
  17. Liu MM, Huang KM, Qian L, Chatterjee P, Zhang S, Li R, Zhou S, Wang Z, Luo Y, Huang Y (2018b) Effects of bioactive constituents in the traditional Chinese medicinal formula Si-Wu-Tang on Nrf2 signaling and neoplastic cellular transformation. Phytomedicine 40:1–9CrossRefGoogle Scholar
  18. Lu Y, Wu X, Dong Y, Xu Z, Zhang Y, Xie Z (2010) Anesthetic sevoflurane causes neurotoxicity differently in neonatal naive and Alzheimer disease transgenic mice. Anesthesiology 112(6):1404–1416CrossRefGoogle Scholar
  19. Lv X, Yan J, Jiang J, Zhou X, Lu Y, Jiang H (2017) MicroRNA-27a-3p suppression of peroxisome proliferator-activated receptor-gamma contributes to cognitive impairments resulting from sevoflurane treatment. J Neurochem 143(3):306–319CrossRefGoogle Scholar
  20. Naidu M, Kuan CYK, Lo WL, Raza M, Tolkovsky A, Mak NK, Wong RNS, Keynes R (2007) Analysis of the action of euxanthone, a plant-derived compound that stimulates neurite outgrowth. Neuroscience 148(4):915–924CrossRefGoogle Scholar
  21. Pan MD, Mao Q (1984) Isolation and identification of wubangziside A and B from Polygala caudata Rehd et Wils. Yao Xue Xue Bao 19(12):899–903Google Scholar
  22. Qu Z, Mossine VV, Cui J, Sun GY, Gu Z (2016) Protective effects of AGE and its components on neuroinflammation and neurodegeneration. NeuroMolecular Med 18(3):474–482CrossRefGoogle Scholar
  23. Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J (2009) Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 110(3):628–637CrossRefGoogle Scholar
  24. Serlin H, Torregrossa MM (2015) Adolescent rats are resistant to forming ethanol seeking habits. Dev Cogn Neurosci 16:183–190CrossRefGoogle Scholar
  25. Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, Sun D, Baxter MG, Zhang Y, Xie Z (2013) Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology 118(3):502–515CrossRefGoogle Scholar
  26. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5(5):415–418CrossRefGoogle Scholar
  27. Smothers CT, Szumlinski KK, Worley PF, Woodward JJ (2016) Altered NMDA receptor function in primary cultures of hippocampal neurons from mice lacking the Homer2 gene. Synapse 70(1):33–39CrossRefGoogle Scholar
  28. Su P, Zhang J, Wang S, Aschner M, Cao Z, Zhao F, Wang D, Chen J, Luo W (2016) Genistein alleviates lead-induced neurotoxicity in vitro and in vivo: involvement of multiple signaling pathways. Neurotoxicology 53:153–164CrossRefGoogle Scholar
  29. Sun L (2010) Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth 105(Suppl 1):i61–i68CrossRefGoogle Scholar
  30. Sun YX, Xu AH, Yang Y, Li J (2015) Role of Nrf2 in bone metabolism. J Biomed Sci 22:101CrossRefGoogle Scholar
  31. Tao G, Zhang J, Zhang L, Dong Y, Yu B, Crosby G, Culley DJ, Zhang Y, Xie Z (2014) Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3beta activation in young mice. Anesthesiology 121(3):510–527CrossRefGoogle Scholar
  32. Thitilertdecha P, Guy RH, Rowan MG (2014) Characterisation of polyphenolic compounds in Clerodendrum petasites S. Moore and their potential for topical delivery through the skin. J Ethnopharmacol 154(2):400–407CrossRefGoogle Scholar
  33. Tian Y, Guo S, Guo Y, Jian L (2015) Anesthetic propofol attenuates apoptosis, Abeta accumulation, and inflammation induced by sevoflurane through NF-kappaB pathway in human neuroglioma cells. Cell Mol Neurobiol 35(6):891–898CrossRefGoogle Scholar
  34. Tian Y, Wu X, Guo S, Ma L, Huang W, Zhao X (2017) Minocycline attenuates sevoflurane-induced cell injury via activation of Nrf2. Int J Mol Med 39(4):869–878CrossRefGoogle Scholar
  35. Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C, Spencer JPE (2008) The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr 3(3–4):115–126CrossRefGoogle Scholar
  36. Wang W, Chen X, Zhang J, Zhao Y, Li S, Tan L, Gao J, Fang X, Luo A (2016) Glycyrrhizin attenuates isoflurane-induced cognitive deficits in neonatal rats via its anti-inflammatory activity. Neuroscience 316:328–336CrossRefGoogle Scholar
  37. Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO (2009) Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 110(4):796–804CrossRefGoogle Scholar
  38. Yu Y, Zhang P, Yan J, Sun Y, Wu X, Xi S, Zhang L, Sun Y, Hu R, Jiang H (2016) Sevoflurane induces cognitive impairments via the MiR-27b/LIMK1-signaling pathway in developing rats. Inhal Toxicol 28(14):731–738CrossRefGoogle Scholar
  39. Yuan H, Jiang C, Zhao J, Zhao Y, Zhang Y, Xu Y, Gao X, Guo L, Liu Y, Liu K, Xu B, Sun G (2018) Euxanthone attenuates Abeta1-42-induced oxidative stress and apoptosis by triggering autophagy. J Mol Neurosci 66(4):512–523CrossRefGoogle Scholar
  40. Zhang DX, Zhang LM, Zhao XC, Sun W (2017a) Neuroprotective effects of erythropoietin against sevoflurane-induced neuronal apoptosis in primary rat cortical neurons involving the EPOR-Erk1/2-Nrf2/Bach1 signal pathway. Biomed Pharmacother 87:332–341CrossRefGoogle Scholar
  41. Zhang LM, Zhang DX, Zhao XC, Sun W (2017b) Erythropoietin rescues primary rat cortical neurons by altering the Nrf2:Bach1 ratio: roles of extracellular signal-regulated kinase 1/2. Neurochem ResGoogle Scholar
  42. Zheng H, Dong Y, Xu Z, Crosby G, Culley DJ, Zhang Y, Xie Z (2013) Sevoflurane anesthesia in pregnant mice induces neurotoxicity in fetal and offspring mice. Anesthesiology 118(3):516–526CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
  2. 2.Department of DermatologyShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina

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