PDF(Pubmed)
Abstract：
Status epilepticus (SE) is a life-threatening disorder that can result in death or severe brain damage, and there is a substantial body of evidence suggesting a strong association between pyroptosis and SE. Sterol regulatory element binding protein 1 (SREBP1) is a significant transcription factor participating in both lipid homeostasis and glucose metabolism. However, the function of SREBP1 in pyroptosis during SE remains unknown. In this study, we established a SE rat model by intraperitoneal injection of lithium chloride and pilocarpine in vivo. Additionally, we treated HT22 hippocampal cells with glutamate to create neuronal injury models in vitro. Our results demonstrated a significant induction of SREBP1, inflammasomes, and pyroptosis in the hippocampus of SE rats and glutamate-treated HT22 cells. Moreover, we found that SREBP1 is regulated by the mTOR signaling pathway, and inhibiting mTOR signaling contributed to the amelioration of SE-induced hippocampal neuron pyroptosis, accompanied by a reduction in SREBP1 expression. Furthermore, we conducted siRNA-mediated knockdown of SREBP1 in HT22 cells and observed a significant reversal of glutamate-induced cell death, activation of inflammasomes, and pyroptosis. Importantly, our confocal immunofluorescence analysis revealed the co-localization of SREBP1 and NLRP1. In conclusion, our findings suggest that deficiency of SREBP1 attenuates glutamate-induced HT22 cell injury and hippocampal neuronal pyroptosis in rats following SE. Targeting SREBP1 may hold promise as a therapeutic strategy for SE.
摘要：
癫痫持续状态（SE）是一种危及生命的疾病，可导致死亡或严重的脑损伤，有大量证据表明焦亡和SE之间有很强的关联。甾醇调节元件结合蛋白1（SREBP1）是参与脂质稳态和葡萄糖代谢的重要转录因子。然而,SREBP1在SE过程中的功能仍不清楚。在这项研究中,我们通过腹腔注射氯化锂和毛果芸香碱建立了SE大鼠模型。此外,我们用谷氨酸处理HT22海马细胞，以建立体外神经元损伤模型。我们的结果表明，SREBP1，炎性体，SE大鼠海马和谷氨酸处理的HT22细胞的焦亡。此外，我们发现SREBP1受mTOR信号通路的调节,抑制mTOR信号有助于改善SE诱导的海马神经元焦亡，伴随着SREBP1表达的减少。此外，我们在HT22细胞中进行了siRNA介导的SREBP1敲低，并观察到谷氨酸诱导的细胞死亡的显着逆转，炎症体的激活，和焦亡。重要的是,我们的共聚焦免疫荧光分析显示SREBP1和NLRP1共定位.总之,我们的发现表明，SREBP1的缺乏减轻了SE后大鼠的谷氨酸诱导的HT22细胞损伤和海马神经元的细胞凋亡。靶向SREBP1可能有望成为SE的治疗策略。
