PDF(Pubmed)
Abstract：
Ferroptosis is an iron-dependent cell death mechanism involving the accumulation of lipid peroxides. As a critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be downregulated in epilepsy. However, the mechanism of ferroptosis in epilepsy remains unclear. In this study, bioinformatics analysis, analysis of epilepsy patient blood samples and cell and mouse experiments revealed strong associations among epilepsy, ferroptosis, microRNA-211-5p and purinergic receptor P2X 7 (P2RX7). P2RX7 is a nonselective ligand-gated homotrimeric cation channel, and its activation mainly increases neuronal activity during epileptic seizures. In our study, the upregulation of P2RX7 in epilepsy was attributed to the downregulation of microRNA (miR)-211-5p. Furthermore, P2RX7 has been found to regulate GPX4/HO-1 by alleviating lipid peroxidation induced by suppression of the MAPK/ERK signaling pathway in murine models. The dynamic decrease in miR-211-5p expression induces hypersynchronization and both nonconvulsive and convulsive seizures, and forebrain miR-211-5p suppression exacerbates long-lasting pentylenetetrazole-induced seizures. Additionally, in this study, induction of miR-211-5p expression or genetic-silencing of P2RX7 significantly reduced the seizure score and duration in murine models through the abovementioned pathways. These results suggest that the miR-211-5p/P2RX7 axis is a novel target for suppressing both ferroptosis and epilepsy.
摘要：
铁凋亡是一种铁依赖性细胞死亡机制，涉及脂质过氧化物的积累。作为一个关键的监管者，谷胱甘肽过氧化物酶4（GPX4）已被证明在癫痫中下调。然而,癫痫中铁凋亡的机制尚不清楚.在这项研究中,生物信息学分析，对癫痫患者血液样本和细胞和小鼠实验的分析揭示了癫痫之间的强烈关联，铁性凋亡,microRNA-211-5p和嘌呤能受体P2X7（P2RX7）。P2RX7是一种非选择性配体门控同三聚体阳离子通道，它的激活主要增加癫痫发作期间的神经元活动。在我们的研究中,癫痫中P2RX7的上调归因于microRNA(miR)-211-5p的下调.此外，已发现P2RX7通过减轻小鼠模型中MAPK/ERK信号通路抑制诱导的脂质过氧化来调节GPX4/HO-1。miR-211-5p表达的动态降低诱导超同步化以及非惊厥性和惊厥性癫痫发作，和前脑miR-211-5p抑制加剧了戊四唑长期诱发的癫痫发作。此外,在这项研究中，miR-211-5p表达的诱导或P2RX7的遗传沉默通过上述途径显著降低小鼠模型中的癫痫发作评分和持续时间。这些结果表明miR-211-5p/P2RX7轴是抑制铁性凋亡和癫痫的新靶标。
