Sevoflurane anesthesia in pregnant rats negatively affects nerve function in offspring potentially via inhibition of the Wnt/β-catenin pathway

Wang,Yiyao; Li,Yu; Xing,Qunzhi; Han,Xuechan  G.; Dong,Xu; Lu,Yiping; Zhou,Mintao

doi:10.3892/mmr.2017.6316

Sevoflurane anesthesia in pregnant rats negatively affects nerve function in offspring potentially via inhibition of the Wnt/β-catenin pathway

Authors:
- Yiyao Wang
- Yu Li
- Qunzhi Xing
- Xuechan G. Han
- Xu Dong
- Yiping Lu
- Mintao Zhou
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Affiliations: Department of Anesthesiology, The First Affiliated Hospital and College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
Published online on: March 13, 2017 https://doi.org/10.3892/mmr.2017.6316
Pages: 2753-2759

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Abstract

Due to the rapid development of medical technology used to perform intrauterine procedures during pregnancy, the number of patients receiving fetal surgery under general anesthesia is increasing. The aim of the present study was to determine the effects of anesthetics on the offspring of rats, and to identify the potential mechanisms underlying these effects. On day 14 of pregnancy, Sprague‑Dawley rats were equally divided into the following 3 groups (n=9): Control group (n=3), 3% sevoflurane group (n=3) and 4% sevoflurane group (n=3). Following birth of the offspring, the juvenile rats were assessed using an open‑field test, Morris water maze and a continuous passive avoidance test on different days to determine their learning abilities and memory. Western blot and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analyses were used to examine the expression of multiple critical factors associated with the proliferation and apoptosis of nerve cells, including Ki67, nestin, B cell leukemia/lymphoma 2 (Bcl-2), BCL2 associated X (Bax) and caspase‑3. Additionally, the level of adenosine triphosphate production among the 3 groups were compared. Furthermore, expression alterations in of glycogen synthase kinase‑3β (GSK‑3β) and β‑catenin were examined. The Morris water maze experiment revealed that an increased concentration of sevoflurane exposure significantly reduced the learning and memory abilities of the juvenile rats when compared with controls. In addition, western blotting and RT-qPCR analyses determined that the protein and mRNA expression levels of Bax, caspase‑3 and GSK‑3β were significantly increased relative to the controls. By contrast, the expression levels of nestin, Ki‑67, Bcl‑2 and β‑catenin were significantly reduced. The results of the present study suggest that exposure of pregnant mice to sevoflurane anesthesia demonstrates a negative effect on the learning and memory abilities of their offspring, and the Wnt/β-catenin signaling pathway may be involved in this process.

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1	Heesen M and Klimek M: Nonobstetric anesthesia during pregnancy. Curr Opin Anaesthesiol. 29:297–303. 2016. View Article : Google Scholar : PubMed/NCBI
2	Owsiak JN and Bullough AS: Chronic myeloid leukemia in pregnancy: An absolute contraindication to neuraxial anesthesia? Int J Obstet Anesth. 25:85–88. 2016. View Article : Google Scholar : PubMed/NCBI
3	Miller TL, Park R and Sun LS: Report on the Fifth PANDA Symposium on ‘Anesthesia and Neurodevelopment in Children’. J Neurosurg Anesthesiol. 28:350–355. 2016. View Article : Google Scholar : PubMed/NCBI
4	Stratmann G: Review article: Neurotoxicity of anesthetic drugs in the developing brain. Anesth Analg. 113:1170–1179. 2011. View Article : Google Scholar : PubMed/NCBI
5	Costi D, Cyna AM, Ahmed S, Stephens K, Strickland P, Ellwood J, Larsson JN, Chooi C, Burgoyne LL and Middleton P: Effects of sevoflurane versus other general anaesthesia on emergence agitation in children. Cochrane Database Syst Rev CD007084. 2014. View Article : Google Scholar
6	Lorsomradee S, Cromheecke S, Lorsomradee S and De Hert SG: Effects of sevoflurane on biomechanical markers of hepatic and renal dysfunction after coronary artery surgery. J Cardiothorac Vasc Anesth. 20:684–690. 2006. View Article : Google Scholar : PubMed/NCBI
7	Head BP and Patel P: Anesthetics and brain protection. Curr Opin Anaesthesiol. 20:395–399. 2007. View Article : Google Scholar : PubMed/NCBI
8	Istaphanous GK, Howard J, Nan X, Hughes EA, McCann JC, McAuliffe JJ, Danzer SC and Loepke AW: Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology. 114:578–587. 2011. View Article : Google Scholar : PubMed/NCBI
9	Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, Sun D, Baxter MG, Zhang Y and Xie Z: Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology. 118:502–515. 2013. View Article : Google Scholar : PubMed/NCBI
10	Li Y, Zeng M, Chen W, Liu C, Wang F, Han X, Zuo Z and Peng S: Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats. PLoS One. 9:e936392014. View Article : Google Scholar : PubMed/NCBI
11	Joksimovic M and Awatramani R: Wnt/β-catenin signaling in midbrain dopaminergic neuron specification and neurogenesis. J Mol Cell Biol. 6:27–33. 2014. View Article : Google Scholar : PubMed/NCBI
12	Parish CL and Thompson LH: Modulating Wnt signaling to improve cell replacement therapy for Parkinson's disease. J Mol Cell Biol. 6:54–63. 2014. View Article : Google Scholar : PubMed/NCBI
13	Lange C, Mix E, Rateitschak K and Rolfs A: Wnt signal pathways and neural stem cell differentiation. Neurodegener Dis. 3:76–86. 2006. View Article : Google Scholar : PubMed/NCBI
14	Dai ZM, Sun S, Wang C, Huang H, Hu X, Zhang Z, Lu QR and Qiu M: Stage-specific regulation of oligodendrocyte development by Wnt/β-catenin signaling. J Neurosci. 34:8467–8473. 2014. View Article : Google Scholar : PubMed/NCBI
15	L'Episcopo F, Tirolo C, Testa N, Caniglia S, Morale MC, Deleidi M, Serapide MF, Pluchino S and Marchetti B: Plasticity of subventricular zone neuroprogenitors in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease involves cross talk between inflammatory and Wnt/β-catenin signaling pathways: Functional consequences for neuroprotection and repair. J Neurosci. 32:2062–2085. 2012. View Article : Google Scholar : PubMed/NCBI
16	Liu H and Lou W: Functioning remobilization of the paralyzed vocal cord using the split-vagus nerve procedure in rats the split-vagus nerve procedure in rats. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 24:273–275. 2010.(In Chinese). PubMed/NCBI
17	Schoenfeld R, Schiffelholz T, Beyer C, Leplow B and Foreman N: Variations of the Morris water maze task to comparatively assess human and rodent place navigation. Neurobiol Learn Mem. 139:117–127. 2017. View Article : Google Scholar : PubMed/NCBI
18	Radahmadi M, Alaei H, Sharifi MR and Hosseini N: Effect of forced exercise and exercise withdrawal on memory, serum and hippocampal corticosterone levels in rats. Exp Brain Res. 233:2789–2799. 2015. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Patel D and Chaudhary J: Increased expression of bHLH transcription factor E2A (TCF3) in prostate cancer promotes proliferation and confers resistance to doxorubicin induced apoptosis. Biochem Biophys Res Commun. 422:146–151. 2012. View Article : Google Scholar : PubMed/NCBI
21	Lerman J, Sikich N, Kleinman S and Yentis S: The pharmacology of sevoflurane in infants and children. Anesthesiology. 80:814–824. 1994. View Article : Google Scholar : PubMed/NCBI
22	Liang G, Ward C, Peng J, Zhao Y, Huang B and Wei H: Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology. 112:1325–1334. 2010. View Article : Google Scholar : PubMed/NCBI
23	Shen X, Liu Y, Xu S, Zhao Q, Guo X, Shen R and Wang F: Early life exposure to sevoflurane impairs adulthood spatial memory in the rat. Neurotoxicology. 39:45–56. 2013. View Article : Google Scholar : PubMed/NCBI
24	Takaenoki Y, Satoh Y, Araki Y, Kodama M, Yonamine R, Yufune S and Kazama T: Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood. Anesthesiology. 120:403–415. 2014. View Article : Google Scholar : PubMed/NCBI
25	Kruger K, Stefansson IM, Collett K, Arnes JB, Aas T and Akslen LA: Microvessel proliferation by co-expression of endothelial nestin and Ki-67 is associated with a basal-like phenotype and aggressive features in breast cancer. Breast. 22:282–288. 2013. View Article : Google Scholar : PubMed/NCBI
26	Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N and Gotoh Y: The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development. 131:2791–2801. 2004. View Article : Google Scholar : PubMed/NCBI
27	Rudloff S and Kemler R: Differential requirements for β-catenin during mouse development. Development. 139:3711–3721. 2012. View Article : Google Scholar : PubMed/NCBI
28	Lupo G, Novorol C, Smith JR, Vallier L, Miranda E, Alexander M, Biagioni S, Pedersen RA and Harris WA: Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/β-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures. Open Biol. 3:1201672013. View Article : Google Scholar : PubMed/NCBI
29	Castelo-Branco G and Arenas E: Function of Wnts in dopaminergic neuron development. Neurodegener Dis. 3:5–11. 2006. View Article : Google Scholar : PubMed/NCBI
30	Cole AR: GSK3 as a Sensor Determining Cell Fate in the Brain. Front Mol Neurosci. 5:42012. View Article : Google Scholar : PubMed/NCBI
31	Fuchs C, Trazzi S, Torricella R, Viggiano R, De Franceschi M, Amendola E, Gross C, Calzà L, Bartesaghi R and Ciani E: Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling. Neurobiol Dis. 70:53–68. 2014. View Article : Google Scholar : PubMed/NCBI
32	Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR and Snider WD: GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci. 12:1390–1397. 2009. View Article : Google Scholar : PubMed/NCBI
33	Morales-Garcia JA, Luna-Medina R, Alonso-Gil S, Sanz-Sancristobal M, Palomo V, Gil C, Santos A, Martinez A and Perez-Castillo A: Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo. ACS Chem Neurosci. 3:963–971. 2012. View Article : Google Scholar : PubMed/NCBI
34	Munji RN, Choe Y, Li G, Siegenthaler JA and Pleasure SJ: Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors. J Neurosci. 31:1676–1687. 2011. View Article : Google Scholar : PubMed/NCBI
35	Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL, Palmer TD and Nusse R: Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci USA. 105:16970–16975. 2008. View Article : Google Scholar : PubMed/NCBI
36	Kunke D, Bryja V, Mygland L, Arenas E and Krauss S: Inhibition of canonical Wnt signaling promotes gliogenesis in P0-NSCs. Biochem Biophys Res Commun. 386:628–633. 2009. View Article : Google Scholar : PubMed/NCBI
37	Galli S, Lopes DM, Ammari R, Kopra J, Millar SE, Gibb A and Salinas PC: Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice. Nat Commun. 5:49922014. View Article : Google Scholar : PubMed/NCBI