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microRNA-139-5p confers sensitivity to antiepileptic drugs in refractory epilepsy by inhibition of MRP1.
CNS Neuroscience & Therapeutics ( IF 5.5 ) Pub Date : 2019-11-21 , DOI: 10.1111/cns.13268
Li Wang 1 , Lifang Song 1 , Xiaoyi Chen 1 , Junfang Suo 1 , Yanli Ma 1 , Jinghe Shi 1 , Kai Liu 1 , Guohong Chen 1
Affiliation  

AIM Drug resistance is an intractable issue urgently needed to be overcome for improving efficiency of antiepileptic drugs in treating refractory epilepsy. microRNAs (miRNAs) have been proved as key regulators and therapeutic targets in epilepsy. Accordingly, the aim of the present study was to identify a novel differentially expressed miRNA which could improve the efficiency of antiepileptic drugs during the treatment of refractory epilepsy. METHODS AND RESULTS Serum samples were collected from children with refractory epilepsy. An in vivo refractory epilepsy model was developed in SD rats by electrical amygdala kindling. We identified that miR-139-5p was decreased and multidrug resistance-associated protein 1 (MRP1) was remarkably upregulated in the serum samples from children with refractory epilepsy and the brain tissues from rat models of refractory epilepsy. After phenobarbitone injection in rat models of refractory epilepsy, the after discharging threshold in kindled amygdala was detected to screen out drug-resistant rats. Dual-luciferase reporter gene assay demonstrated that MRP1 was a target of miR-139-5p. In order to evaluate the effect of miR-139-5p/MRP1 axis on drug resistance of refractory epilepsy, we transfected plasmids into the hippocampus of drug-resistant rats to alter the expression of miR-139-5p and MRP1. TUNEL staining and Nissl staining showed that miR-139-5p overexpression or MRP1 downregulation could reduce the apoptosis and promote survival of neurons, accompanied by alleviated neuronal damage. CONCLUSION Collectively, these results suggest an important role of miR-139-5p/MRP1 axis in reducing the resistance of refractory epilepsy to antiepileptic drugs.

中文翻译:

microRNA-139-5p 通过抑制 MRP1 赋予难治性癫痫患者对抗癫痫药物的敏感性。

目的 耐药性是提高抗癫痫药物治疗难治性癫痫疗效急需攻克的难题。microRNAs (miRNAs) 已被证明是癫痫的关键调节因子和治疗靶点。因此,本研究的目的是鉴定一种新的差异表达 miRNA,它可以提高抗癫痫药物治疗难治性癫痫的疗效。方法和结果 血清样本采集自难治性癫痫患儿。通过杏仁核电点燃法在SD大鼠体内建立了难治性癫痫模型。我们发现难治性癫痫患儿的血清样本和难治性癫痫大鼠模型的脑组织中 miR-139-5p 降低,多药耐药相关蛋白 1 (MRP1) 显着上调。难治性癫痫大鼠模型注射苯巴比妥后,检测点燃杏仁核后放电阈值,筛选耐药大鼠。双荧光素酶报告基因检测表明 MRP1 是 miR-139-5p 的靶标。为了评估 miR-139-5p/MRP1 轴对难治性癫痫耐药的影响,我们将质粒转染到耐药大鼠的海马中,以改变 miR-139-5p 和 MRP1 的表达。TUNEL染色和Nissl染色显示miR-139-5p过表达或MRP1下调可减少细胞凋亡并促进神经元存活,同时减轻神经元损伤。结论 总的来说,这些结果表明 miR-139-5p/MRP1 轴在降低难治性癫痫对抗癫痫药物的耐药性中具有重要作用。
更新日期:2019-11-21
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