Department of Neurology, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, China.
Fujian Provincial Key Laboratory of Neurodegenerative Diseases and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.
Neuroimmunomodulation. 2019;26(2):67-76. doi: 10.1159/000496344. Epub 2019 Mar 29.
OBJECTIVE(S): Neuroinflammation is an important contributor to the development of seizures and epilepsy. Micro-RNA-155 (miR-155) plays a critical role in immunity and -inflammation. This study aims to explore the function of miR-155 and miR-155-mediated inflammation in epilepsy.
About 8-week-old male C57BL/6 mice were administered an intraperitoneal injection (i.p.) of kainic acid (KA) (15 mg/kg) or saline. The mice in the KA group developing acute seizure were further subjected to intracerebroventricular injection (i.c.v.) of antagomir negative control (NC) or miR-155 antagomir. Animal behavior was observed according to Racine's scale, and electroencephalographs were recorded. Primary microglia were cultured and treated with antagomir NC or antagomir. Whole-cell electrophysiological recording was conducted to detect the spontaneous EPSCs and IPSCs in the neurons treated with different conditioned medium from those microglia. miR-155 were detected by qRT-PCR in those models, as well as in the brain or blood from epileptic patients and healthy controls.
miR-155 was abundantly expressed in glial cells compared with neurons, and its expression was markedly elevated in the brain of epilepsy patients and KA-induced seizure mice. Silencing miR-155 attenuated KA-induced seizure, abnormal electroencephalography, proinflammatory cytokine expression, and microglia morphology change. Moreover, conditioned media from KA-treated microglia impaired neuron excitability, whereas conditioned media from KA and miR-155 antagomir co-treated microglia had no such effects. Finally, miR-155 levels were significantly higher in the blood of epilepsy patients than those of healthy controls.
CONCLUSION(S): These findings demonstrate that aberrant upregulation of miR-155 contributes to epileptogenesis through inducing microglia neuroinflammation.
神经炎症是癫痫发作和癫痫发展的重要原因。微小 RNA-155（miR-155）在免疫和炎症中起着关键作用。本研究旨在探讨 miR-155 的功能及其在癫痫中的炎症作用。
约 8 周龄雄性 C57BL/6 小鼠腹腔注射（i.p.）海人酸（KA）（15mg/kg）或生理盐水。KA 组急性发作癫痫的小鼠进一步进行侧脑室注射（i.c.v.）阴性对照（NC）或 miR-155 拮抗剂。根据 Racine 量表观察动物行为，并记录脑电图。培养原代小胶质细胞并分别用 NC 拮抗剂或 miR-155 拮抗剂处理。对不同条件培养基处理的神经元进行全细胞电生理记录，检测神经元的自发性 EPSCs 和 IPSCs。采用 qRT-PCR 检测这些模型以及癫痫患者和健康对照者大脑或血液中的 miR-155。
miR-155 在神经胶质细胞中的表达量明显高于神经元，在癫痫患者和 KA 诱导癫痫发作的小鼠大脑中表达明显上调。沉默 miR-155 可减轻 KA 诱导的癫痫发作、异常脑电图、促炎细胞因子表达和小胶质细胞形态变化。此外，来自 KA 处理的小胶质细胞的条件培养基损害神经元兴奋性，而来自 KA 和 miR-155 拮抗剂共同处理的小胶质细胞的条件培养基则没有这种作用。最后，癫痫患者血液中的 miR-155 水平明显高于健康对照组。
这些发现表明，miR-155 的异常上调通过诱导小胶质细胞神经炎症导致癫痫发生。
