母体暴露于挥发性麻醉剂会在胎儿大脑中诱导产生白细胞介素-6,并影响神经元发育。

Maternal exposure to volatile anesthetics induces IL-6 in fetal brains and affects neuronal development.

机构信息

Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Department of Anesthesia, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto, 612-0861, Japan.

出版信息

Eur J Pharmacol. 2019 Nov 15;863:172682. doi: 10.1016/j.ejphar.2019.172682. Epub 2019 Sep 20.

Abstract

Most clinically used general anesthetics have demonstrated neurotoxicity in animal studies, but the related mechanisms remain unknown. Previous studies suggest that anesthetics affect neuronal development through neuroinflammation, and significant effects of neuroinflammation on neurogenesis and neuronal disease have been shown. In the present study, we treated pregnant mice with 2% sevoflurane for 3 h at gestational day 15.5 and analyzed the expression of proinflammatory cytokines, including IL-6 and IL-17, in fetal mice brains. Sevoflurane induced IL-6 mRNA significantly, but did not upregulate IL-17. Other volatile anesthetics, including isoflurane, enflurane, and halothane, induced IL-6 mRNA in fetal brains as well as sevoflurane, but propofol did not. Sevoflurane and isoflurane showed the same effects in cultured microglia and astrocytes, but not in neurons. Because IL-6 induction in fetal brains may affect neuronal precursor cells (NPCs), numbers of NPCs in the subventricular zone were studied, revealing that maternal sevoflurane treatment significantly increases NPCs in offspring at 8 weeks after birth (p8wk). But this effect was absent in IL-6 knockout mice. Finally, behavioral experiments also revealed that maternal sevoflurane exposure causes learning impairments in p8wk offspring. These findings collectively demonstrate that maternal exposure to volatile anesthetics upregulates IL-6 in fetal mice brains, and the effects could result in long-lasting influences on neuronal development.

摘要

大多数临床上使用的全身麻醉药在动物研究中表现出神经毒性,但相关机制尚不清楚。先前的研究表明,麻醉剂通过神经炎症影响神经元发育,并且已经证明神经炎症对神经发生和神经元疾病有重大影响。在本研究中,我们在妊娠第 15.5 天用 2%七氟醚处理怀孕的老鼠 3 小时,并分析胎鼠大脑中促炎细胞因子(包括 IL-6 和 IL-17)的表达。七氟醚显著诱导 IL-6 mRNA,但未上调 IL-17。其他挥发性麻醉剂,包括异氟烷、恩氟烷和氟烷,与七氟醚一样,在胎鼠脑中诱导了 IL-6 mRNA,但丙泊酚没有。七氟醚和异氟醚在培养的小胶质细胞和星形胶质细胞中均有相同的作用,但在神经元中没有。因为胎鼠脑中的 IL-6 诱导可能影响神经前体细胞(NPCs),所以研究了室下区 NPCs 的数量,结果表明母鼠七氟醚处理后,出生后 8 周(p8wk)的后代 NPCs 数量明显增加(p8wk)。但在 IL-6 基因敲除小鼠中没有这种效果。最后,行为实验也表明,母鼠接触七氟醚会导致 p8wk 后代的学习障碍。这些发现共同表明,母体暴露于挥发性麻醉剂会使胎鼠脑中的 IL-6 上调,并且这种作用可能会对神经元发育产生持久影响。

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