Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Neurosurgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
J Cell Mol Med. 2020 Nov;24(22):12980-12993. doi: 10.1111/jcmm.15894. Epub 2020 Oct 1.
Epilepsy is a chronic brain disease characterized by recurrent seizures. Circular RNA (circRNA) is a novel family of endogenous non-coding RNAs that have been proposed to regulate gene expression. However, there is a lack of data on the role of circRNA in epilepsy. In this study, the circRNA profiles were evaluated by microarray analysis. In total, 627 circRNAs were up-regulated, whereas 892 were down-regulated in the hippocampus in mice with kainic acid (KA)-induced epileptic seizures compared with control. The expression of circHivep2 was significantly down-regulated in hippocampus tissues of mice with KA-induced epileptic seizures and BV-2 microglia cells upon KA treatment. Bioinformatics analysis predicted that circHivep2 interacts with miR-181a-5p to regulate SOCS2 expression, which was validated using a dual-luciferase reporter assay. Moreover, overexpression of circHivep2 significantly inhibited KA-induced microglial activation and the expression of inflammatory factors in vitro, which was blocked by miR-181a-5p, whereas circHivep2 knockdown further induced microglia cell activation and the release of pro-inflammatory proteins in BV-2 microglia cells after KA treatment. The application of circHivep2+ exosomes derived from adipose-derived stem cells (ADSCs) exerted significant beneficial effects on the behavioural seizure scores of mice with KA-induced epilepsy compared to control exosomes. The circHivep2+ exosomes also inhibited microglial activation, the expression of inflammatory factors, and the miR-181a-5p/SOCS2 axis in vivo. Our results suggest that circHivep2 regulates microglia activation in the progression of epilepsy by interfering with miR-181a-5p to promote SOCS2 expression, indicating that circHivep2 may serve as a therapeutic tool to prevent the development of epilepsy.
癫痫是一种以反复发作性癫痫发作为特征的慢性脑部疾病。环状 RNA（circRNA）是一类新的内源性非编码 RNA，据推测其可以调节基因表达。然而，circRNA 在癫痫中的作用尚缺乏相关数据。本研究通过微阵列分析评估了 circRNA 谱。与对照组相比，在红藻氨酸（KA）诱导的癫痫发作的小鼠海马中，有 627 个 circRNA 上调，892 个 circRNA 下调。在 KA 诱导的癫痫发作的小鼠海马组织和 KA 处理的 BV-2 小胶质细胞中，circHivep2 的表达明显下调。生物信息学分析预测 circHivep2 与 miR-181a-5p 相互作用以调节 SOCS2 表达，该预测通过双荧光素酶报告基因检测得到验证。此外，circHivep2 的过表达在体外显著抑制 KA 诱导的小胶质细胞激活和炎症因子表达，而 miR-181a-5p 阻断了这种作用，而 circHivep2 的敲低则进一步诱导 KA 处理后的 BV-2 小胶质细胞激活和促炎蛋白释放。与对照 exosomes 相比，脂肪来源干细胞（ADSCs）衍生的 circHivep2+exosomes 对 KA 诱导癫痫小鼠的行为癫痫评分具有显著的有益作用。circHivep2+exosomes 还抑制了体内小胶质细胞激活、炎症因子表达以及 miR-181a-5p/SOCS2 轴。我们的研究结果表明，circHivep2 通过干扰 miR-181a-5p 促进 SOCS2 表达来调节癫痫进展中的小胶质细胞激活，提示 circHivep2 可能作为一种治疗工具来预防癫痫的发生。
