Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Int J Mol Sci. 2017 Sep 7;18(9):1925. doi: 10.3390/ijms18091925.
Neuronal injury due to seizures may result from a mismatch of energy demand and adenosine triphosphate (ATP) synthesis. However, ATP demand and oxygen consumption rates have not been accurately determined, yet, for different patterns of epileptic activity, such as interictal and ictal events. We studied interictal-like and seizure-like epileptiform activity induced by the GABA antagonist bicuculline alone, and with co-application of the M-current blocker XE-991, in rat hippocampal slices. Metabolic changes were investigated based on recording partial oxygen pressure, extracellular potassium concentration, and intracellular flavine adenine dinucleotide (FAD) redox potential. Recorded data were used to calculate oxygen consumption and relative ATP consumption rates, cellular ATP depletion, and changes in FAD/FADH₂ ratio by applying a reactive-diffusion and a two compartment metabolic model. Oxygen-consumption rates were ca. five times higher during seizure activity than interictal activity. Additionally, ATP consumption was higher during seizure activity (94% above control) than interictal activity (15% above control). Modeling of FAD transients based on partial pressure of oxygen recordings confirmed increased energy demand during both seizure and interictal activity and predicted actual FAD autofluorescence recordings, thereby validating the model. Quantifying metabolic alterations during epileptiform activity has translational relevance as it may help to understand the contribution of energy supply and demand mismatches to seizure-induced injury.
癫痫发作引起的神经元损伤可能是由于能量需求与三磷酸腺苷（ATP）合成不匹配所致。然而，对于不同的癫痫活动模式，如发作间期和发作期，ATP 的需求和耗氧量尚未得到准确确定。我们研究了单独使用 GABA 拮抗剂荷包牡丹碱以及与 M 电流阻断剂 XE-991 共同应用时，在大鼠海马切片中诱导的发作样和发作样癫痫样活动。基于记录部分氧分压、细胞外钾浓度和黄素腺嘌呤二核苷酸（FAD）氧化还原电势来研究代谢变化。通过应用反应扩散和两室代谢模型来计算氧耗和相对 ATP 耗率、细胞内 ATP 耗竭以及 FAD/FADH₂ 比的变化。与发作间期活动相比，发作活动期间的耗氧量约高 5 倍。此外，与发作间期活动（比对照高约 15%）相比，发作活动期间的 ATP 消耗更高（比对照高约 94%）。基于氧分压记录的 FAD 瞬态建模证实了在发作和发作间期活动期间能量需求增加，并预测了实际的 FAD 自发荧光记录，从而验证了该模型。量化癫痫样活动期间的代谢改变具有转化相关性，因为它可能有助于了解能量供应和需求不匹配对癫痫发作引起的损伤的贡献。
