PDF(Pubmed)
Abstract：
UNASSIGNED: Levetiracetam (LEV) has been found to have an antihyperalgesic effect via acting on the adenosine system. However, the effects of LEV on the modulation of the adenosine system in the brain have not been elucidated in the prevention of seizures and epilepsy. The present study aimed to explore the possible LEV mechanisms of action in the adenosine signaling systems in an animal model of epilepsy.
UNASSIGNED: A docking study was initially performed to determine the possible interaction of LEV with adenosine A1 receptors (A1Rs) and equilibrative nucleoside transporters-1 (ENT1). The experimental study was divided into an acute seizure test (32 mice distributed into 4 groups) and a chronic kindling model study (40 mice distributed into 5 groups), followed by gene expression analysis and immunohistochemistry. The kindling model lasted 26 days and took 13 subconvulsive doses of pentylenetetrazole (PTZ) to completely kindle the mice in the PTZ control group. Gene expression changes in the A1Rs, potassium inwardly-rectifying channel 3.2 (Kir3.2), and ENT1 in the brain tissue samples of the mice following treatment with LEV were analyzed using reverse transcription-quantitative polymerase chain reaction, and immunohistochemistry was performed for the A1R protein expression.
UNASSIGNED: Docking studies predicted a significant interaction of LEV with A1Rs and ENT1 proteins. Results from the acute testing revealed that caffeine (100 mg/kg) and 8-cyclopentyl-1,3-dipropylxanthine (25 mg/kg) significantly reversed the antiseizure effects of LEV by reversing the percent protection and shortening the onset of the first myoclonic jerk (FMJ) and generalized clonic seizures (GCSs). In the PTZ-induced kindling, LEV demonstrated an increased gene expression of A1Rs and Kir3.2 in the brain. LEV also significantly reduced the gene expression of ENT1. Furthermore, the immunohistochemical analysis showed that LEV increased the protein expression of A1Rs in the brain.
UNASSIGNED: Based on these results, it can be concluded that LEV modulates epileptogenesis by acting on the adenosine pathway in the central nervous system.
UNASSIGNED: A docking study was initially performed to determine the possible interaction of LEV with adenosine A1 receptors (A1Rs) and equilibrative nucleoside transporters-1 (ENT1). The experimental study was divided into an acute seizure test (32 mice distributed into 4 groups) and a chronic kindling model study (40 mice distributed into 5 groups), followed by gene expression analysis and immunohistochemistry. The kindling model lasted 26 days and took 13 subconvulsive doses of pentylenetetrazole (PTZ) to completely kindle the mice in the PTZ control group. Gene expression changes in the A1Rs, potassium inwardly-rectifying channel 3.2 (Kir3.2), and ENT1 in the brain tissue samples of the mice following treatment with LEV were analyzed using reverse transcription-quantitative polymerase chain reaction, and immunohistochemistry was performed for the A1R protein expression.
UNASSIGNED: Docking studies predicted a significant interaction of LEV with A1Rs and ENT1 proteins. Results from the acute testing revealed that caffeine (100 mg/kg) and 8-cyclopentyl-1,3-dipropylxanthine (25 mg/kg) significantly reversed the antiseizure effects of LEV by reversing the percent protection and shortening the onset of the first myoclonic jerk (FMJ) and generalized clonic seizures (GCSs). In the PTZ-induced kindling, LEV demonstrated an increased gene expression of A1Rs and Kir3.2 in the brain. LEV also significantly reduced the gene expression of ENT1. Furthermore, the immunohistochemical analysis showed that LEV increased the protein expression of A1Rs in the brain.
UNASSIGNED: Based on these results, it can be concluded that LEV modulates epileptogenesis by acting on the adenosine pathway in the central nervous system.
摘要：
■已发现左乙拉西坦（LEV）通过作用于腺苷系统而具有抗痛觉过敏作用。然而,LEV对脑中腺苷系统调节的影响在预防癫痫发作和癫痫中尚未阐明。本研究旨在探讨LEV在癫痫动物模型腺苷信号传导系统中的可能作用机制。
■最初进行了对接研究，以确定LEV与腺苷A1受体（A1R）和平衡核苷转运蛋白-1（ENT1）的可能相互作用。实验研究分为急性癫痫发作试验(32只小鼠分为4组)和慢性点燃模型研究(40只小鼠分为5组),随后进行基因表达分析和免疫组织化学。点燃模型持续26天，并服用13次惊厥剂量的戊四唑（PTZ）以完全点燃PTZ对照组的小鼠。A1Rs基因表达变化,钾向内整流通道3.2(Kir3.2)，使用逆转录-定量聚合酶链反应分析LEV处理后小鼠脑组织样品中的ENT1，并对A1R蛋白表达进行免疫组织化学。
■对接研究预测了LEV与A1R和ENT1蛋白的显著相互作用。急性测试结果表明，咖啡因（100mg/kg）和8-环戊基-1,3-二丙基黄嘌呤（25mg/kg）通过逆转保护百分比和缩短首次肌阵挛性发作的发作显着逆转了LEV的抗癫痫作用（FMJ）和全身性阵挛性癫痫发作（GCSs）。在PTZ引起的点燃中，LEV显示脑中A1R和Kir3.2的基因表达增加。LEV也显著降低ENT1的基因表达。此外，免疫组织化学分析显示LEV增加了脑内A1Rs的蛋白表达。
■基于这些结果，可以得出结论，LEV通过作用于中枢神经系统的腺苷通路来调节癫痫的发生。
■最初进行了对接研究，以确定LEV与腺苷A1受体（A1R）和平衡核苷转运蛋白-1（ENT1）的可能相互作用。实验研究分为急性癫痫发作试验(32只小鼠分为4组)和慢性点燃模型研究(40只小鼠分为5组),随后进行基因表达分析和免疫组织化学。点燃模型持续26天，并服用13次惊厥剂量的戊四唑（PTZ）以完全点燃PTZ对照组的小鼠。A1Rs基因表达变化,钾向内整流通道3.2(Kir3.2)，使用逆转录-定量聚合酶链反应分析LEV处理后小鼠脑组织样品中的ENT1，并对A1R蛋白表达进行免疫组织化学。
■对接研究预测了LEV与A1R和ENT1蛋白的显著相互作用。急性测试结果表明，咖啡因（100mg/kg）和8-环戊基-1,3-二丙基黄嘌呤（25mg/kg）通过逆转保护百分比和缩短首次肌阵挛性发作的发作显着逆转了LEV的抗癫痫作用（FMJ）和全身性阵挛性癫痫发作（GCSs）。在PTZ引起的点燃中，LEV显示脑中A1R和Kir3.2的基因表达增加。LEV也显著降低ENT1的基因表达。此外，免疫组织化学分析显示LEV增加了脑内A1Rs的蛋白表达。
■基于这些结果，可以得出结论，LEV通过作用于中枢神经系统的腺苷通路来调节癫痫的发生。
