Status epilepticus (SE) is defined as continuous seizure activity lasting more than 5 minutes. It results in neuronal cell death, mediated by endoplasmic reticulum (ER) stress response. Previously, metformin demonstrated neuroprotective effects in primary cortical neurons. In this study, we analyzed the effect of metformin on ER stress via the pro-apoptotic protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. SE was induced in rats by pentylenetetrazole. Following SE, the rats were treated with salubrinal, GSK2656157, or metformin. In a control group (normal saline) SE was not induced. CHOP, eIF2α, and PERK expression was determined by Western blot; apoptosis was analyzed by TUNEL assay. CHOP expression was significantly increased at 6 and 24 hours following SE. At both time points, eIF2α and PERK levels were also increased. At 6 hours, CHOP expression was significantly reduced in salubrinal, GSK2656157 and metformin groups versus SE group. eIF2α and PERK levels were decreased in metformin compared to SE group. eIF2α expression was markedly decreased in salubrinal versus SE group, while PERK expression was markedly reduced in GSK2656157 versus SE group. At 6 and 24 hours, the apoptosis rate was significantly increased in SE versus control group, while it was significantly reduced in salubrinal, GSK2656157, and metformin groups compared to SE group. The apoptosis rate also decreased in salubrinal group at 24 hours, although not to the extent observed in metformin group. Overall, CHOP expression and apoptosis induced by SE in rats were reduced with metformin. Further studies are required to evaluate the clinical relevance of metformin for patients with SE.

中文翻译：

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二甲双胍治疗通过PERK-eIF2α-CHOP途径对癫痫持续状态（SE）诱导的内质网（ER）应激的影响。

癫痫持续状态（SE）定义为持续发作超过5分钟。它导致神经元细胞死亡，由内质网（ER）应激反应介导。以前，二甲双胍对原代皮层神经元具有神经保护作用。在这项研究中，我们通过促凋亡蛋白激酶RNA样内质网激酶（PERK）-真核起始因子2α（eIF2α）-C / EBP同源蛋白（CHOP）途径分析了二甲双胍对内质网应激的影响。戊四氮可在大鼠体内诱发SE。SE后，大鼠用salubrinal，GSK2656157或二甲双胍治疗。在对照组（生理盐水）中未诱导SE。通过蛋白质印迹法确定CHOP，eIF2α和PERK表达；通过TUNEL测定法分析细胞凋亡。SE后6和24小时，CHOP表达显着增加。在两个时间点，eIF2α和PERK水平也均升高。与SE组相比，salubrinal，GSK2656157和二甲双胍组在6小时时CHOP表达显着降低。与SE组相比，二甲双胍的eIF2α和PERK水平降低。与SE组相比，salulalinaleIF2α表达明显降低，而GSK2656157与SE组相比，PERK表达显着降低。与SE组相比，SE与对照组相比，在第6和24小时，凋亡率显着增加，而在salulbrinal，GSK2656157和metformin组中，凋亡率显着降低。尽管在二甲双胍组中未观察到这种程度，但在24小时时，salubinal组的凋亡率也降低了。总体而言，二甲双胍可减少SE诱导的SEOP表达和细胞凋亡。