Sigma-1受体别构调节剂SOMCL-668抗癫痫作用及其机制的研究

Recent studies have shown that sigma-1 receptor may be an excellent target for the development of new antiepileptic drugs. We have found SOMCL-668 is a high-selective, high potent sigma-1 receptor allosteric modulator. Our primary study indicated that SOMCL-668 (20, 40 mg/kg) can effectively alleviate the tonic seizure induced by electrical stimulus; meanwhile, it didn’t alter the spontaneous activity and the motor coordination in mice, which means that SOMCL-668 is a potential antiepileptic drug. Besides, we also found that SOMCL-668 promotes the translocation of sigma-1 receptor from the endoplasmic reticulum to the plasma membrane. Based on these data, we will 1) examine the antiepileptic effect of SOMCL-668 on various kinds of seizures, 2) expound the mechanism of the sigma-1 receptor membrane translocation induced by SOMCL-668 and 3) test the influence of the sigma-1 receptor membrane translocation on the Kv1.x K+ current. Our project will not only reveal the antiepileptic characteristics of SOMCL-668, but also further elucidate the molecular mechanism.

Sigma-1受体已成为新型抗癫痫药物的开发靶点之一。我们发现了一类高活性、高选择的sigma-1受体别构剂，其代表性化合物为SOMCL-668。初步实验显示，SOMCL-668能抗拮抗电休克诱发的强直性癫痫发作，并且不影响小鼠的自发活动和协调能力，进而提示sigma-1受体别构调节剂是一类潜在的抗癫痫药物。另外，我们还发现SOMCL-668能够促使sigma-1从内质网向细胞膜转位。本课题将此为基础，深入研究：1)SOMCL-668对各类不同类型的癫痫发作的影响；2)sigma-1受体膜转位在癫痫中的作用及SOMCL-668促进sigma-1膜转位的分子机制；3)sigma-1受体膜转位对Kv1.x电流及细胞兴奋性的影响。这一研究不仅系统阐明SOMCL-668抗癫痫作用的特点，同时也深入研究了其抗癫痫作用的分子机制。

本项目旨在研究sigma-1受体别构调节剂SKF83959和SOMCL-668抗癫痫作用与机制。我们首先应用最大电休克模型、戊四氮诱导癫痫阵挛模型、海人藻酸诱导的癫痫持续状态模型，确定了其抗癫痫效应。该类化合物还可以抑制大脑皮层的癫痫样放电和高钾诱导的海马脑片的癫痫样放电。SKF83959和SOMCL的抗癫痫作用呈现相加效应。我们还发现了SOMCL-668能够促进内质网上sigma-1受体与Bip分子的解离，并向细胞膜迁移，促进神经元轴突生长。而这一效应与其抑制信号分子GSK-3β的磷酸化密切相关。另外，我们发现，sigma-1受体别构调节剂能够抑制促炎症因子TNF-α、 IL-1β、iNOS的表达，抑制反应氧的产生，抑制炎症因子介导的神经毒性。Sigma-1受体拮抗剂BD1047 及ketoconazole可以抑制上述效应。这说明sigma-1受体别构调节剂的抗炎效应依赖于sigma-1受体的激活和内源性DHEA的合成。该部分内容是我们的最新发现。我们这些研究结果能够进一步解释sigma-1受体别构调节剂的抗癫痫效应及其他生物学效应。项目资助发表SCI论文4篇。培养博士研究生2名，硕士生1名。