Fu Meng, Zhu Yiqing, Zhang Junqi, Wu Wei, Sun Yunxia, Zhang Xuemei, Tao Jie, Li Zhiping
Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
Front Pharmacol. 2021 Aug 23;12:714556. doi: 10.3389/fphar.2021.714556. eCollection 2021.
One-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE). Valproic acid (VPA) is a classic anticonvulsant drug, and its resistance is a crucial predictor of DRE, but the pathogenesis remain unknown. Most patients with VPA-resistant epilepsy appear distinct inflammatory response and local hypoxia. Hypoxia-inducible factor (HIF)-1α is an essential effector molecule of hypoxia and inflammation, and may exert therefore a significant effect on the development of VPA-resistant epilepsy. We systematically assess the significance of HIF-1α on children and mice with VPA-resistant epilepsy, and investigated the micro (mi) RNAs that regulate HIF-1α expression. We established models of VPA-sensitive epilepsy and VPA-resistant epilepsy in mice, and confirmed that they had significant differences in epileptic behavior and electroencephalography data. Through proteomics analysis, we identified that HIF-1α was overexpressed in mice with VPA-resistant epilepsy, and regulated the expression of interleukin-1β and tumor necrosis factor-α. Increased expression of HIF-1α led to the increase of microglia and induced their polarization from the M2 phenotype to M1 phenotype, which triggered the release of proinflammatory mediators. Bioinformatics analysis of public databases demonstrated that miR-221-3p was reduced in VPA-resistant epilepsy, and negatively regulated HIF-1α expression. Intervention using miR-221-3p mimics reduced HIF-1α expression markedly and suppressed the activation of microglia and the release of inflammatory mediators, which relieved epileptic seizures of VPA-resistant epilepsy. These observations reveal miR-221-3p/HIF-1α as essential component in pathogenesis of VPA-resistant epilepsy which represent therapeutic antiseizure targets.
三分之一的癫痫患者患有耐药性癫痫（DRE）。丙戊酸（VPA）是一种经典的抗惊厥药物，其耐药性是DRE的关键预测指标，但其发病机制尚不清楚。大多数VPA耐药性癫痫患者表现出明显的炎症反应和局部缺氧。缺氧诱导因子（HIF）-1α是缺氧和炎症的重要效应分子，因此可能对VPA耐药性癫痫的发展产生显著影响。我们系统地评估了HIF-1α对VPA耐药性癫痫儿童和小鼠的意义，并研究了调节HIF-1α表达的微小（mi）RNA。我们在小鼠中建立了VPA敏感性癫痫和VPA耐药性癫痫模型，并证实它们在癫痫行为和脑电图数据方面存在显著差异。通过蛋白质组学分析，我们发现HIF-1α在VPA耐药性癫痫小鼠中过表达，并调节白细胞介素-1β和肿瘤坏死因子-α的表达。HIF-1α表达增加导致小胶质细胞增多，并诱导其从M2表型向M1表型极化，从而触发促炎介质的释放。对公共数据库的生物信息学分析表明，miR-221-3p在VPA耐药性癫痫中减少，并负向调节HIF-1α表达。使用miR-221-3p模拟物进行干预可显著降低HIF-1α表达，并抑制小胶质细胞的激活和炎症介质的释放，从而缓解VPA耐药性癫痫的癫痫发作。这些观察结果揭示了miR-221-3p/HIF-1α是VPA耐药性癫痫发病机制中的重要组成部分，代表了治疗癫痫发作的靶点。
