Persistent mitoK_ATP Activation Is Involved in the Isoflurane-induced Cytotoxicity

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• 作者：Yan Yang ; Xiufang Chen ; Haiyan Min ; Shiyu Song ; Juan Zhang…
• 关键词：Isoflurane ; MitoKATP ; Cytotoxicity ; ROS ; Intellicage
• 刊名：Molecular Neurobiology
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：54
• 期：2
• 页码：1101-1110
• 全文大小：
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182
• 卷排序：54

文摘

Isoflurane exposure induces apoptosis in cultured cells and in the developing brain, while the underlying mechanism remains largely unclarified. This study was designed to determine whether the disruption of mitoK_ATP-mediated ATP balance was involved in the cytotoxicity of isoflurane. Human neuroglioma cells U251 and 7-day-old mice were treated with isoflurane. A specific mitoK_ATP antagonist 5-HD was used, and the cellular ATP levels, NAD+/NADH ratios, and mitochondrial transmembrane potential (ΔΨ_m) were measured. Our data showed that the blockage of mitoK_ATP by 5-HD mitigated the isoflurane-induced ΔΨ_m disruption, reactive oxygen species (ROS) accumulation, and apoptosis in U251 cells. Moreover, we found that the toxic effect of isoflurane was not observed in the first 2-h exposure; instead, the cellular ATP levels and NAD+/NADH ratios were markedly increased. The reduction of ATP levels and NAD+/NADH ratios was only detected after this initial phase. This dynamical effect of isoflurane was blocked by 5-HD. In contrast, a ROS scavenger NAC sustained the isoflurane-induced ATP elevation. Similar results were observed in animal studies. And again, 5-HD attenuated isoflurane-induced cognitive disorders in the Intellicage test, a system that assesses place learning behavior in a social environment. Our study uncovered a potential mechanism underlying isoflurane’s toxicity with a therapeutic future.