Pichardo Macías Luz Adriana, Ramírez Mendiola Blanca Alcira, Contreras García Itzel Jatziri, Zamudio Hernández Sergio Roberto, Chávez Pacheco Juan Luis, Sánchez Huerta Karla Berenice, Mendoza Torreblanca Julieta Griselda
Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, CDMX, México; Laboratorio de Neurociencias del Instituto Nacional de Pediatría, CDMX, México.
Laboratorio de Farmacología del Instituto Nacional de Pediatría, CDMX, México.
Epilepsy Res. 2018 Feb;140:111-119. doi: 10.1016/j.eplepsyres.2018.01.004. Epub 2018 Jan 5.
Levetiracetam (LEV) is an anticonvulsant drug with a unique mechanism of action that is not completely understood. However, its activity profile may involve effects on excitatory and/or inhibitory neurotransmission since the primary target of LEV, synaptic vesicle protein 2A, is ubiquitously expressed in all types of synaptic vesicles. Therefore, the objective of the present study was to explore the effect of LEV (300 mg/kg/day for one week, administered via osmotic mini-pumps) on neurotransmitter release and its probable selective effect on extracellular gamma-amino butyric acid (GABA), glutamate (Glu), aspartate (Asp), glutamine (Gln), taurine (Tau) and glycine (Gly) concentrations (using in vivo microdialysis under basal and high-K conditions) in the dorsal hippocampus (DH), a region that undergoes major synaptic changes during epilepsy. Epileptic rats developed clear signs of hyperexcitability, i.e., an elevated Glu/GABA ratio in the DH. The LEV concentration in blood after 7 days of treatment was within the therapeutic range. In contrast, LEV was not detected four days after mini-pump removal (washout period). Furthermore, LEV restored the Glu/GABA ratio to approximately the control level and significantly increased the GABA concentration after the initiation of high-K conditions. Based on these data, LEV treatment restored the lost balance between the excitatory and inhibitory systems under basal conditions. Moreover, LEV showed a selective effect by preferentially increasing vesicular release of GABA, a mechanism by which LEV could reduce epileptic seizures.
左乙拉西坦（LEV）是一种抗惊厥药物，其作用机制独特，尚未完全明确。然而，其活性特征可能涉及对兴奋性和/或抑制性神经传递的影响，因为LEV的主要靶点——突触囊泡蛋白2A在所有类型的突触囊泡中普遍表达。因此，本研究的目的是探讨LEV（通过渗透微型泵给药，300mg/kg/天，持续一周）对神经递质释放的影响，以及其对癫痫发作期间经历主要突触变化的背侧海马区（DH）细胞外γ-氨基丁酸（GABA）、谷氨酸（Glu）、天冬氨酸（Asp）、谷氨酰胺（Gln）、牛磺酸（Tau）和甘氨酸（Gly）浓度的可能选择性作用（在基础和高钾条件下使用体内微透析法）。癫痫大鼠出现明显的过度兴奋迹象，即DH中的Glu/GABA比值升高。治疗7天后血液中的LEV浓度在治疗范围内。相反，在移除微型泵后四天（洗脱期）未检测到LEV。此外，在高钾条件开始后，LEV将Glu/GABA比值恢复到大致对照水平，并显著提高了GABA浓度。基于这些数据，LEV治疗恢复了基础条件下兴奋性和抑制性系统之间失去的平衡。此外，LEV通过优先增加GABA的囊泡释放显示出选择性作用，这是LEV可以减少癫痫发作的一种机制。
