Zhou Xu, Chen Jun, Tao Hua, Cai Yujie, Huang Lidan, Zhou Haihong, Chen Yanyan, Cui Lili, Zhong Wangtao, Li Keshen
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China.
Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, People's Republic of China.
Neuropsychiatr Dis Treat. 2020 May 20;16:1295-1307. doi: 10.2147/NDT.S247677. eCollection 2020.
To confront the resistance to existing antiepileptic drugs, studies have gradually begun to investigate alternative pathologies distinct from the traditional treatments that overwhelmingly target ion channels. Microglia activation is the first inflammatory response in the brain, in which miR-155-5p plays a key proinflammatory role and thus represents a promising target for inflammatory modulation in epilepsy pathologies.
In this study, a pentetrazol-induced acute seizure model was established, and the seizure degree was evaluated within 60 min after pentetrazol administration. Animals were then sacrificed for hippocampal tissue collection for biological experiments.
Intranasal delivery of miR-155-5p antagomir (30 min before pentetrazol administration) increased the percentage of animals with no induced seizures by 20%, extended the latency to generalized convulsions, and decreased seizure severity. In addition, miR-155-5p antagomir treatment alleviated hippocampal damage and decreased the expression of typical inflammatory modulators (TNF-α, IL-1β and IL-6). Further research revealed that intranasal delivery of miR-155-5p antagomir significantly decreased the relative level of miR-155-5p and increased the expression of its targets LXRα and SOCS1 in IBA1-labeled microglial cells in the hippocampus.
These findings demonstrate that intranasal delivery of miR-155-5p antagomir alleviated acute seizures, likely by blocking hippocampal inflammation. However, other potential mechanisms of the effects of miR-155-5p antagomir and its long-term safety for epilepsy treatment remain to be investigated.
为应对对现有抗癫痫药物的耐药性，研究已逐渐开始探索与传统的主要针对离子通道的治疗方法不同的其他病理机制。小胶质细胞激活是大脑中的首个炎症反应，其中miR-155-5p发挥关键的促炎作用，因此是癫痫病理中炎症调节的一个有前景的靶点。
在本研究中，建立了戊四氮诱导的急性癫痫模型，并在给予戊四氮后60分钟内评估癫痫发作程度。然后处死动物以收集海马组织用于生物学实验。
鼻内给予miR-155-5p拮抗剂（在给予戊四氮前30分钟）使未诱发癫痫发作的动物百分比增加了20%，延长了全身惊厥的潜伏期，并降低了癫痫发作严重程度。此外，miR-155-5p拮抗剂治疗减轻了海马损伤，并降低了典型炎症调节因子（TNF-α、IL-1β和IL-6）的表达。进一步研究表明，鼻内给予miR-155-5p拮抗剂显著降低了海马中IBA1标记的小胶质细胞中miR-155-5p的相对水平，并增加了其靶标LXRα和SOCS1的表达。
这些发现表明，鼻内给予miR-155-5p拮抗剂可能通过阻断海马炎症减轻急性癫痫发作。然而，miR-155-5p拮抗剂作用的其他潜在机制及其对癫痫治疗的长期安全性仍有待研究。
