Department of Neurology, University of Wisconsin , Madison, Wisconsin.
William S. Middleton Memorial Veterans Hospital , Madison, Wisconsin.
J Neurophysiol. 2019 Apr 1;121(4):1092-1101. doi: 10.1152/jn.00723.2018. Epub 2019 Jan 23.
2-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG's acute effects on synaptic and membrane properties of CA3 pyramidal neurons in vitro. 2DG (10 mM) had no effects on spontaneously occurring postsynaptic currents (PSCs) in 3.5 mM extracellular potassium concentration ([K]). In 7.5 mM [K], 2DG significantly reduced the frequency of epileptiform bursting and the charge carried by postsynaptic currents (PSCs) with a greater effect on inward excitatory compared with outward inhibitory charge (71% vs. 40%). In 7.5 mM [K] and bicuculline, 2DG reduced significantly the excitatory charge by 67% and decreased the frequency but not amplitude of excitatory PSCs between bursts. In 7.5 mM [K], 2DG reduced pharmacologically isolated inhibitory PSC frequency without a change in amplitude. The frequency but not amplitude of inward miniature PSCs was reduced when 2DG was applied in 7.5 mM [K] before bath application of TTX, but there was no effect when 2DG was applied after TTX, indicating a use-dependent uptake of 2DG was required for its actions at a presynaptic locus. 2DG did not alter membrane properties of CA3 neurons except for reducing the slow afterhyperpolarization in 3.5 but not 7.5 mM [K]. The reduction in frequency of spontaneous and inward miniature PSCs in elevated [K] indicates a presynaptic mechanism of action. 2DG effects required use-dependent uptake and suggest an important role for glycolysis in neuronal metabolism and energetics in states of high neural activity as occur during abnormal network synchronization and seizures. NEW & NOTEWORTHY 2-Deoxy-d-glucose (2DG) is a glycolytic inhibitor and suppresses epileptiform activity acutely and has chronic antiepileptic effects. The mechanisms of the acute effects are not well delineated. In this study, we show 2DG suppressed abnormal network epileptiform activity without effecting normal synaptic network activity or membrane properties. The effects appear to be use dependent and have a presynaptic locus of action. Inhibition of glycolysis is a novel presynaptic mechanism to limit abnormal neuronal network activity and seizures.
2-脱氧-D-葡萄糖（2DG）是一种葡萄糖类似物，可抑制糖酵解，具有急性和慢性抗癫痫作用。我们评估了 2DG 在体外对 CA3 锥体神经元突触和膜特性的急性作用。在 3.5 mM 细胞外钾浓度（[K]）下，2DG 对自发发生的突触后电流（PSC）没有影响。在 7.5 mM [K]下，2DG 显著降低癫痫样爆发的频率和突触后电流（PSC）携带的电荷量，对内源性兴奋性的作用大于对外源性抑制性的作用（71%比 40%）。在 7.5 mM [K]和荷包牡丹碱中，2DG 使兴奋性电荷量显著减少 67%，并降低爆发之间兴奋性 PSC 的频率但不影响振幅。在 7.5 mM [K]下，2DG 降低了药理学分离的抑制性 PSC 频率，而不改变振幅。当 2DG 在 7.5 mM [K]中施加于浴液中的 TTX 之前时，内向微小 PSC 的频率降低，但幅度不变，但当 2DG 在 TTX 之后施加时没有影响，表明其作用部位的摄取依赖于 2DG 的使用。2DG 除了降低 3.5 mM [K]而不是 7.5 mM [K]中的慢后超极化外，不改变 CA3 神经元的膜特性。在高钾条件下，自发和内向微小 PSC 的频率降低表明存在突触前作用机制。2DG 作用需要使用依赖性摄取，并表明糖酵解在神经元代谢和高能状态下的能量代谢中起重要作用，这种状态发生在异常网络同步和癫痫发作期间。新的和值得注意的是，2-脱氧-D-葡萄糖（2DG）是一种糖酵解抑制剂，可抑制癫痫样活动，并具有急性抗癫痫作用，且具有慢性抗癫痫作用。急性作用的机制尚未明确。在这项研究中，我们表明 2DG 抑制异常网络癫痫样活动而不影响正常的突触网络活动或膜特性。这些作用似乎是使用依赖性的，具有突触前作用部位。糖酵解抑制是一种限制异常神经元网络活动和癫痫发作的新的突触前机制。
