Gram L, Larsson O M, Johnsen A H, Schousboe A
University Clinic of Neurology, Hvidovre Hospital, Denmark.
Epilepsy Res. 1988 Mar-Apr;2(2):87-95. doi: 10.1016/0920-1211(88)90024-1.
Valproate (VPA) and vigabatrin (gamma-vinyl GABA, GVG) are two novel antiepileptic drugs with a presumed GABAergic mechanism of action. However, for VPA, this aspect has been extensively debated. The aim of the present study was to investigate whether treatment of cultured neurons with clinically relevant concentrations of VPA and GVG might enhance release of endogenous GABA. In order to address the question of the fate of released GABA, studies involving exogenous, radiolabeled GABA were also undertaken. Exposure of neurons to GVG in a concentration range of 10-300 microM led to a significant increase in the cellular GABA content, whereas concentrations of VPA of 30-300 microM had no such effect. Treatment of the neurons with concentrations of GVG as low as 25 microM resulted in a pronounced increase in evoked release of endogenous GABA, compared to controls. Only high concentrations of VPA (300 microM) caused an increase in the synaptic GABA release, which reached statistical significance. Preincubating the neurons with exogenously labeled GABA in the presence of GVG or aminooxyacetic acid, both of which block GABA metabolism, caused a decrease in the specific radioactivity in the cellular GABA pool. This, together with the observation that the specific radioactivity of the releasable GABA pool always exceeded that of the cellular pool, indicates that exogenously supplied GABA preferentially labels the transmitter pool of GABA.
丙戊酸盐（VPA）和氨己烯酸（γ - 乙烯基 - GABA，GVG）是两种作用机制推测为通过γ-氨基丁酸（GABA）能的新型抗癫痫药物。然而，对于VPA而言，这一方面一直存在广泛争议。本研究的目的是调查用临床相关浓度的VPA和GVG处理培养的神经元是否会增强内源性GABA的释放。为了解决释放的GABA的去向问题，还进行了涉及外源性放射性标记GABA的研究。将神经元暴露于浓度范围为10 - 300微摩尔/升的GVG中会导致细胞内GABA含量显著增加，而30 - 300微摩尔/升的VPA浓度则没有这种作用。与对照组相比，用低至25微摩尔/升的GVG浓度处理神经元会导致内源性GABA的诱发释放显著增加。只有高浓度的VPA（300微摩尔/升）会导致突触GABA释放增加，且达到统计学显著水平。在存在GVG或氨氧基乙酸（两者均阻断GABA代谢）的情况下，用外源性标记的GABA对神经元进行预孵育，会导致细胞内GABA池的比放射性降低。这一点，连同可释放GABA池的比放射性总是超过细胞池的比放射性这一观察结果，表明外源性提供的GABA优先标记GABA的递质池。
