Sigma-1受体别构激动剂调控神经炎症抑制“癫痫发生”进程的研究

Epileptogenesis is the gradual process that a normal brain develops epilepsy after various injuries. The structure and function of neurons are changed gradually during the process of epileptogenesis, and the spontaneous seizures occur ultimately. It is regrettable that the current therapeutic methods could not inhibit the process of epileptogenesis. Recently, it is found that the neuroinflammation induced by microglia promotes the process of epileptogenesis. We have identified a series of sigma-1 allosteric agonists, in which SKF83959 and SOMCL-668 are two representative agonists. In the primary studies, we found that SKF83959 and SOMCL-668 inhibited the process of epileptogenesis, independent of their anti-seizure effect. Besides, we found that SKF83959 and SOMCL-668 could inhibit LPS-induced activation of microglia in vitro. Based on these findings, we will 1) deeply examine how sigma-1 allosteric agonists， SKF83959 and SOMCL-668， affect the epileptic behavior, the epileptic discharge in electroencephalogram, the state of neuroinflammation, the activation and infiltration of microglia in the murine “epileptogenesis” models; 2) observe the inhibiting effect of the two sigma-1 allosteric agonists on the activation and migration of microglia in experiment in vitro; 3) examine the influence of the two sigma-1 allosteric agonists on the signal pathway of intracellular Ca2+ oscillation/ calcineurin/Akt/GSK-3βin microglia; 4) establish the role of the Ca2+ oscillation/calcineurin/Akt/GSK-3β signal pathway in the anti-epileptogenic activity of the two sigma-1 allosteric agonists. Our research will not only expound the anti-epileptogenic action of sigma-1 allosteric agonists, but also illustrate their acting molecular mechanism, and provide new ideas and targets for epilepsy treatment as well.

“癫痫发生”指大脑受到伤害以后，结构和功能发生变化，神经元活动异常，出现反复自发性癫痫发作的过程。近年研究发现，小胶质细胞介导的神经炎症在“癫痫发生”中起着重要作用。我们发现了一类高活性、高选择性的sigma-1受体别构激动剂，其代表化合物SKF83959和SOMCL-668，均能调节神经炎症，抑制“癫痫发生”的进程。以此为基础，本课题将深入研究：（1)上述化合物对啮齿类动物“癫痫发生”模型的自发性癫痫发作、脑内癫痫样放电、炎症介质的影响；（2)对体内外小胶质细胞活化、迁移、浸润的影响；（3）对小胶质细胞内Ca2+振荡/calcineurin/Akt/糖原合成酶-3β信号通路的作用；（4)确认该信号通路在上述化合物抑制“癫痫发生”中的作用。这一研究不仅系统阐明sigma-1受体别构激动剂抑制“癫痫发生”的药理效应，而且深入研究其分子作用机制，为癫痫治疗提供新的思路和靶点。

有效抑制“癫痫发生”进程及癫痫并发症是癫痫治疗领域急需解决的问题。我们以往的研究发现了一类以SKF83959为代表的sigma-1别构调节剂，并初步确定了该类化合物具有抗“癫痫发生”和改善癫痫并发症的潜能。. 本项目在此为基础，系统研究了sigma-1受体别构调节剂抗“癫痫发生”的效应及分子机制。我们发现了（1）SKF83959具有延缓癫痫发生，缓解海马神经元损伤、胶质结节形成，抑制神经炎症，并且改善癫痫所导致的认知功能障碍和抑郁状态；（2）SKF83959的保护作用依赖于海马内源性的脱氢表雄酮，SKF83959通过增强内源性脱氢表雄酮的生理作用而起到抗癫痫效应；（3）Ca2+振荡/Calcineurin/GSK-3β信号通路是小胶质细胞活化的非经典信号通路；SKF83959的抗神经炎症效应与其抑制上述信号通路有关。另外，我们还鉴别了一类sigma-1受体效应蛋白，即TAMM41，提出了sigma-1受体-TAMM41轴的概念，确定了sigma-1受体-TAMM41轴在癫痫发病中作用及潜在的治疗价值。. 我们这些研究结果不仅阐明了sigma-1受体别构调节剂抗“癫痫发生”的效应与分子机制，有助于后续的sigma-1受体别构调节剂的医学转化研究，还提出了新的具有抗癫痫效应的靶点，为癫痫治疗提供了新的方向。. 在项目执行期间，共发表学术论文5篇，其中SCI收录4篇；申请国家发明专利2项；培养硕士研究生3名，其中两名已获得硕士学位。