Wang Yuan, Yin Shao-Wei, Zhang Nan, Zhao Ping
Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
Department of Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
Neural Regen Res. 2018 Sep;13(9):1575-1584. doi: 10.4103/1673-5374.237121.
Sevoflurane is the most commonly used volatile anesthetic during pregnancy. The viability of neural stem cells directly affects the development of the brain. However, it is unknown whether the use of sevoflurane during the second trimester affects the survival of fetal neural stem cells. Therefore, in this study, we investigated whether exposure to sevoflurane in mid-gestation induces apoptosis of neural stem cells and behavioral abnormalities. On gestational day 14, pregnant rats were anesthetized with 2% or 3.5% sevoflurane for 2 hours. The offspring were weaned at 28 days and subjected to the Morris water maze test. The brains were harvested to examine neural stem cell apoptosis by immunofluorescence and to measure Nestin and SOX-2 levels by western blot assay at 6, 24 and 48 hours after anesthesia as well as on postnatal day (P) 0, 14 and 28. Vascular endothelial growth factor (VEGF) and phosphoinositide 3-kinase (PI3K)/AKT pathway protein levels in fetal brain at 6 hours after anesthesia were assessed by western blot assay. Exposure to high-concentration (3.5%) sevoflurane during mid-gestation increased escape latency and path length to the platform, and it reduced the average duration spent in the target quadrant and platform crossing times. At 6, 24 and 48 hours after anesthesia and at P0, P14 and P28, the percentage of Nestin/terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells was increased, but Nestin and SOX-2 protein levels were decreased in the hippocampus of the offspring. At 6 hours after anesthesia, VEGF, PI3K and phospho-AKT (p-AKT) levels were decreased in the fetal brain. These changes were not observed in animals given low-concentration (2%) sevoflurane exposure. Together, our findings indicate that exposure to a high concentration of sevoflurane (3.5%) in mid-gestation decreases VEGF, PI3K and p-AKT protein levels and induces neural stem cell apoptosis, thereby causing learning and memory dysfunction in the offspring.
七氟醚是孕期最常用的挥发性麻醉剂。神经干细胞的活力直接影响大脑发育。然而，妊娠中期使用七氟醚是否会影响胎儿神经干细胞的存活尚不清楚。因此，在本研究中，我们调查了妊娠中期暴露于七氟醚是否会诱导神经干细胞凋亡和行为异常。在妊娠第14天，将怀孕大鼠用2%或3.5%的七氟醚麻醉2小时。子代在28日断奶，并进行莫里斯水迷宫试验。在麻醉后6、24和48小时以及出生后第（P）0、14和28天收获大脑，通过免疫荧光检查神经干细胞凋亡，并通过蛋白质免疫印迹法测量巢蛋白（Nestin）和性别决定区Y框蛋白2（SOX-2）水平。通过蛋白质免疫印迹法评估麻醉后6小时胎儿脑中血管内皮生长因子（VEGF）和磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路蛋白水平。妊娠中期暴露于高浓度（3.5%）七氟醚会增加逃避潜伏期和到达平台的路径长度，并减少在目标象限花费的平均持续时间和穿越平台的次数。在麻醉后6、24和48小时以及P0、P14和P28时，子代海马中巢蛋白/末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）阳性细胞的百分比增加，但巢蛋白和SOX-2蛋白水平降低。麻醉后6小时，胎儿脑中VEGF、PI3K和磷酸化AKT（p-AKT）水平降低。在低浓度（2%）七氟醚暴露的动物中未观察到这些变化。总之，我们的研究结果表明，妊娠中期暴露于高浓度（3.5%）七氟醚会降低VEGF、PI3K和p-AKT蛋白水平，并诱导神经干细胞凋亡，从而导致子代学习和记忆功能障碍。
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