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Effects of Sevoflurane on Self-Renewal Capacity and Differentiation of Cultured Neural Stem Cells

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Abstract

Sevoflurane anesthesia in infant rats can result in long-term cognitive impairment, possibly by inhibiting neurogenesis. The hippocampus is critical for memory consolidation and is one of only two mammalian brain regions where neural stem cells (NSCs) are renewed continuously throughout life. To elucidate the pathogenesis of sevoflurane-induced cognitive dysfunction, we measured the effects of clinical sevoflurane doses on the survival, proliferation, and differentiation of hippocampal NSCs. Neural stem cells were isolated from Sprague–Dawley rat embryos, expanded in vitro, and exposed to sevoflurane at 0.5, 1, or 1.5 minimal alveolar concentration (MAC) for 1 or 6 h. Two days after treatment, cell viability, cytotoxicity, and apoptosis rate were estimated by WST-1 assay, lactate dehydrogenase (LDH) activity, and TdT-mediated dUTP-biotin nick end labeling (TUNEL), respectively, while proliferation rate was assessed by 5-ethynyl-2′-deoxyuridine (BrdU) incorporation and Ki67 staining. Differentiation was assayed 7 days after treatment by immunocytochemistry and Western blots of neuron and glial markers. The phosphorylation level of p44/42 extracellular regulated kinases (ERK1/2) was measured in the proliferation and differentiation phases respectively. Sevoflurane at 1 MAC or 1.5 MAC for 1 h increased viable cell number whereas a 6 h exposure at these same concentrations suppressed proliferation and promoted apoptotic death (P < 0.01). Sevoflurane had no effect on NSC differentiation, and a sub-clinical concentration (0.5 MAC) altered neither proliferation nor viability. The phosphorylation level of ERK1/2 increased after 1 h of 1 MAC or 1.5 MAC of sevoflurane exposure in the proliferation phase, but not in the differentiation phase. Brief (1 h) exposure to sevoflurane at clinical concentrations enhanced proliferation of cultured NSCs possibly mediated by ERK1/2, but a 6 h exposure suppressed proliferation and induced apoptosis. Prolonged sevoflurane exposure may decrease the self-renewal capacity of hippocampal NSCs, resulting in cognitive deficits.

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Acknowledgments

This work was supported by the National Science Foundation for Distinguished Scientists of the State Key Program of National Natural Science Foundation of China (Grant 30930091 to Lize Xiong) and from the National Natural Science Foundation of China (Grant 30972853 to HaiLong Dong). We thank Dr. Bairen Wang (Professor, Institute of Neuroscience, Fourth Military Medical University, Xi’an Shaanxi, China) for reviewing the manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, China

    Huang Nie, Ning Lao, Hailong Dong & Lize Xiong

  2. Department of Psychosomatic Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, China

    Zhengwu Peng

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  1. Huang Nie
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  2. Zhengwu Peng
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  3. Ning Lao
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  4. Hailong Dong
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  5. Lize Xiong
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Correspondence to Hailong Dong or Lize Xiong.

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Huang Nie and Zhengwu Peng contributed equally to the work.

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Nie, H., Peng, Z., Lao, N. et al. Effects of Sevoflurane on Self-Renewal Capacity and Differentiation of Cultured Neural Stem Cells. Neurochem Res 38, 1758–1767 (2013). https://doi.org/10.1007/s11064-013-1074-4

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  • DOI: https://doi.org/10.1007/s11064-013-1074-4

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