Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage
Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage
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DOI：
10.1093/toxsci/kfv150
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发表时间：
2015-10-01
影响因子：
3.8
通讯作者：
Han, Xianlin
中科院分区：
文献类型：
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作者：
Liu, Fang;Rainosek, Shuo W.;Han, Xianlin
七氟醚是一种挥发性麻醉剂，已广泛用于全身麻醉，但其在儿童使用的安全性是公众关注的问题。本研究旨在评估幼猴长期暴露于临床相关浓度的七氟醚是否与发育中的大脑产生任何不良影响有关。将幼猴暴露于2.5%七氟醚中9小时，收集额叶皮质组织进行DNA微阵列、脂质组学、Luminex蛋白和组织学分析。DNA微阵列分析表明，七氟醚暴露导致猴子大脑中差异表达基因（DEGs）的广泛鉴定。一般来说，这些基因与神经系统发育、功能和神经细胞活力有关。值得注意的是，许多deg与脂质代谢密切相关。脂质组学分析表明，关键的脂质成分（如磷脂酰乙醇胺、磷脂酰丝氨酸和磷脂酰甘油）在长时间暴露于七氟醚后显著下调。Luminex蛋白分析表明，七氟醚暴露的大脑中细胞因子水平异常。氟- jade C染色一致显示七氟烷暴露后更多的退化神经元。这些数据表明，临床相关浓度的七氟醚（2.5%）能够在发育中的非人灵长类动物中诱导和维持有效的手术麻醉平面，并且长时间暴露于麻醉平面9小时会导致基因表达、细胞因子水平、脂质代谢以及随后的神经元损伤发生深刻变化。通常，七氟醚诱导的神经元损伤也与脂质含量、组成或两者的变化有关；特定的脂质变化可以为麻醉诱导的神经毒性的分子机制提供见解，并且可能是早期检测麻醉诱导的神经元损伤的敏感生物标志物。
Sevoflurane is a volatile anesthetic that has been widely used in general anesthesia, yet its safety in pediatric use is a public concern. This study sought to evaluate whether prolonged exposure of infant monkeys to a clinically relevant concentration of sevoflurane is associated with any adverse effects on the developing brain. Infant monkeys were exposed to 2.5% sevoflurane for 9 h, and frontal cortical tissues were harvested for DNA microarray, lipidomics, Luminex protein, and histological assays. DNA microarray analysis showed that sevoflurane exposure resulted in a broad identification of differentially expressed genes (DEGs) in the monkey brain. In general, these genes were associated with nervous system development, function, and neural cell viability. Notably, a number of DEGs were closely related to lipid metabolism. Lipidomic analysis demonstrated that critical lipid components, (eg, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol) were significantly downregulated by prolonged exposure of sevoflurane. Luminex protein analysis indicated abnormal levels of cytokines in sevoflurane-exposed brains. Consistently, Fluoro-Jade C staining revealed more degenerating neurons after sevoflurane exposure. These data demonstrate that a clinically relevant concentration of sevoflurane (2.5%) is capable of inducing and maintaining an effective surgical plane of anesthesia in the developing nonhuman primate and that a prolonged exposure of 9h resulted in profound changes in gene expression, cytokine levels, lipid metabolism, and subsequently, neuronal damage. Generally, sevoflurane-induced neuronal damage was also associated with changes in lipid content, composition, or both; and specific lipid changes could provide insights into the molecular mechanism(s) underlying anesthetic-induced neurotoxicity and may be sensitive biomarkers for the early detection of anesthetic-induced neuronal damage.