title: Persistent mitoKATPActivation Is Involved in the Isoflurane-induced Cytotoxicity.
abstract: 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 mitoKATP-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 mitoKATPantagonist 5-HD was used, and the cellular ATP levels, NAD+/NADH ratios, and mitochondrial transmembrane potential (ΔΨm) were measured. Our data showed that the blockage of mitoKATPby 5-HD mitigated the isoflurane-induced ΔΨmdisruption, 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.
authors.affiliation: Department of Anesthesiology, Affiliated Drum-Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 2100093, China.|Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Min
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Anesthesiology, Affiliated Drum-Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 2100093, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Fan
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China.
authors.forename: Long
authors.initials: L
authors.lastname: Yi
authors.affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Affiliated Drum-Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 2100093, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, Affiliated Drum-Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 2100093, China. mazhengliang1964@nju.edu.cn.
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Affiliated Drum-Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 2100093, China. qian_gao@nju.edu.cn.|Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China. qian_gao@nju.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000280:Administration, Inhalation; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D007530:Isoflurane / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D003603:Cytotoxins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D007530:Isoflurane
keywords: Cytotoxicity; Intellicage; Isoflurane; MitoKATP; ROS