徐州医科大学王允团队发现环状RNA hsa_circ_0000288通过结合并稳定caprin1蛋白来预防小鼠癫痫。该项研究成果发表在2025年2月17日出版的《中国药理学报》上。

在这项研究中，课题组在缓解期癫痫患者中发现了抑制癫痫发作的环状RNA。通过比较缓解期和非缓解期患者外周血清中circRNAs的差异表达谱，课题组人员发现hsa_circ_0000288 （circ288）的水平在缓解期癫痫患者中显著升高。课题组建立了凯尼克酸诱导的小鼠癫痫发作模型。通过向海马注射腺相关病毒(AAV)- Circ288过表达载体，可显著改善癫痫诱导的神经元损伤，促进海马神经发生，抑制新生神经元向齿状丘的异常迁移。

此外，circ288过表达显著降低了癫痫发生慢性期的癫痫样放电和自发性发作，减轻了癫痫小鼠的情绪障碍（焦虑、抑郁）和认知缺陷。小组发现circ288直接与RNA 结合蛋白caprin1结合并抑制其降解。在体外癫痫模型中，circ288的保护作用被caprin1敲除逆转，在神经元特异性caprin1敲除小鼠（CaMK2α-Cre:Caprin1^f/f）中丧失。circ288或caprin1的过表达提高了NMDA受体负调剂NMDA受体3B的mRNA水平，提示carpin1-NMDA受体3B通路参与了circ288的作用。考虑到virthem过表达circ288的缺点，该课题组构建了外泌体封装的circ288 (EXO-circ288)，并证明了尾静脉注射EXO-circ288具有良好的保护作用。该研究为开发抗癫痫治疗性RNA 提供了新的途径。

据介绍，目前的抗癫痫药物仍不令人满意，需要新的治疗方法。环状RNA是一类很有前途的治疗性RNA。近年来的研究表明环状RNA在癫痫的病理过程中的作用。

附：英文原文

Title: Circular RNA hsa_circ_0000288 protects against epilepsy in mice by binding to and stabilizing caprin1 protein

Author: Guo, Lin, Lv, Na, Ji, Jian-lun, Gao, Ce, Liu, Si-yu, Liu, Zi-yu, Lin, Xin-ting, Liu, Zhi-dong, Wang, Yun

Issue&Volume: 2025-02-17

Abstract: Current anti-epileptic drugs remain to be unsatisfactory, new therapeutic approaches are needed. Circular RNA is a promising class of therapeutic RNAs. Recent studies have shown the role of circRNA in the pathologic process of epilepsy. In this study, we identified the circRNA in epileptic patients in remission that inhibited the epileptic course. By comparing the profiles of differentially expressed circRNAs in peripheral serum between patients in remission and those not in remission, we found that the level of hsa_circ_0000288 (circ288) was markedly elevated in the epileptic patients in remission. We established a kainic acid-induced status epilepticus model in mice. Overexpression of Circ288 by injecting adeno-associated virus (AAV)-circ288-overexpression vector into hippocampi significantly ameliorated epilepsy-induced neuronal injury, promoted hippocampus neurogenesis, and inhibited abnormal migration of newborn neurons into the dentate hilus. Moreover, circ288 overexpression significantly decreased the epileptiform discharges and the spontaneous seizures in the chronic phase of epileptogenesis and alleviated mood disorders (anxiety, depression), and cognitive deficits in epileptic mice. We revealed that circ288 directly bound to an RNA-binding protein caprin1 and inhibited its degradation. The protective action of circ288 was reversed by the knockdown of caprin1 in an in vitro epileptic model and lost in the neuron-specific caprin1 knockout mice (CaMK2α-Cre:Caprin1^f/f). Overexpression of circ288 or caprin1 raised the mRNA level of NMDA receptor 3B, a negative modulator of NMDA receptors, suggesting the involvement of the carpin1-NMDA receptor 3B pathway in the role of circ288. Given the disadvantages of circ288 overexpression by a virus, we constructed exosomes-encapsulated circ288 (EXO-circ288) and demonstrated that tail vein injection of EXO-circ288 exerted robust protective effects. This study provides a new avenue for developing anti-epileptic therapeutic RNAs.

DOI: 10.1038/s41401-025-01486-x

Source: https://www.nature.com/articles/s41401-025-01486-x