癫痫持续状态（SE）是常见致死性神经危重症。脑水肿和血脑屏障（BBB）损害是继发性损害，也是引起SE难以控制的重要机制，但目前无有效的治疗药物。近年来发现脑损害时新组成的SUR1-TRPM4通道在脑水肿和BBB损害中起重要作用，国内外研究和我们的系列工作发现SUR1-TRPM4抑制剂格列本脲在不同的CNS疾病中有减轻脑水肿和保护BBB的作用。我们的前期研究工作发现，锂-匹罗卡品诱导的SE可升高SUR1和TRPM4的表达，格列本脲可明显减轻SE大鼠的脑水肿并改善预后。本课题拟在多种SE动物模型上进一步验证格列本脲的治疗作用；研究SE后SUR1-TRPM4的表达情况，并通过敲除Trpm4基因等方法研究SUR1-TRPM4的诱导性表达在SE发生和发展中的作用；在脑片和细胞模型上验证低剂量的格列本脲是否对脑组织中的SUR1-TRPM4具有选择性抑制作用，为格列本脲治疗SE的临床转化提供实验基础。

Status epilepticus (SE) is a common fatal emergent and critically neurological disease. Brain edema and blood-brain barrier (BBB) disruption are not only the secondary damage after SE, but also the key causes to hardly terminate seizures. However, effective treatment for brain edema and BBB disruption caused by SE remains unavailable. SUR1-TRPM4 is a cation channel which is de novo expressed after brain injury. In recent years, studies have found that SUR1-TRPM4 plays an important role in BBB disruption and brain edema formation. Current researches as well as our series works have shown that glibenclamide, an inhibitor of SUR1-TRPM4 channel, can reduce brain edema and protect BBB in multiple central nervous system diseases. However, the relationship between SUR1-TRPM4 expression and pathophysiology of SE is unknown. Our preliminary experiments have found that the expression of SUR1 and TRPM4 is up-regulated in a lithium-pilocarpine rat model and low-dose glibenclamide can improve the prognosis of SE. The main contents of this project will include: further confirming the neuroprotective effect of glibenclamide using different animal models of SE; studying the expression of SUR1-TRPM4 after SE and clarifying how the SUR1-TRPM4 channel influences the development of SE using Trpm4 knockout mice, etc; confirming the selective inhibitory effect of low-dose glibenclamide on SUR1-TRPM4 using brain slices and cell model, etc. This project will provide evidence for clinical translation of glibenclamide on SE patients.