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 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 mitoKATP antagonist 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 mitoKATP by 5-HD mitigated the isoflurane-induced ΔΨm 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.