Abstract：
Epilepsy is a chronic neurological disease with recurrent seizures. Increasing evidence suggests that endoplasmic reticulum (ER) stress may play a role in the pathogenesis of epilepsy. We aimed to investigate the effects of Tauroursodeoxycholic acid (TUDCA) and 4-phenyl-butyric acid (4-PBA), which are known to suppress ER stress, on developed seizures in terms of markers of ER stress, oxidative stress, and apoptosis. The pentylenetetrazole (PTZ) kindling model was induced in Wistar albino rats (n = 48) by administering 35 mg/kg PTZ intraperitoneally (I.P.) every other day for 1 month. TUDCA and 4-PBA were administered via I.P. at a dose of 500 mg/kg dose. ER stress, apoptosis, and oxidative stress were determined in the hippocampus tissues of animals in all groups. Immunohistochemistry, qRT-PCR, ELISA, and Western Blot analyzes were performed to determine the efficacy of treatments. Expressions of ATF4, ATF6, p-JNK1/2, Cleaved-Kaspase3, and Caspase12 significantly increased in PTZ-kindled seizures compared to the control group. Increased NOX2 and MDA activity in the seizures were measured. In addition, stereology analyzes showed an increased neuronal loss in the PTZ-kindled group. qRT-PCR examination showed relative mRNA levels of CHOP. Accordingly, TUDCA and 4-PBA treatment suppressed the expressions of ATF4, ATF6, Cleaved-Caspase3, Kaspase12, NOX2, MDA, and CHOP in TUDCA + PTZ and 4-PBA + PTZ groups. ER stress-induced oxidative stress and apoptosis by reducing neuronal loss and degeneration were also preserved in these groups. Our data show molecularly that TUDCA and 4-PBA treatment can suppress the ER stress process in epileptic seizures.
摘要：
癫痫是一种慢性神经系统疾病，反复发作。越来越多的证据表明，内质网（ER）应激可能在癫痫的发病机制中起作用。我们旨在研究牛磺熊去氧胆酸（TUDCA）和4-苯基丁酸（4-PBA）的作用，已知可以抑制ER压力，根据内质网应激的标志物，氧化应激，和凋亡。在Wistar白化病大鼠（n=48）中，每隔一天腹膜内（I.P.）施用35mg/kgPTZ，持续1个月，以诱导戊四氮（PTZ）点燃模型。通过I.P.以500mg/kg剂量的剂量施用TUDCA和4-PBA。ER压力,凋亡，并测定各组动物海马组织的氧化应激。免疫组织化学,qRT-PCR,ELISA,进行Western印迹分析以确定治疗的功效。与对照组相比，PTZ点燃性癫痫发作中ATF4，ATF6，p-JNK1/2，Cleaved-Kaspase3和Caspase12的表达显着增加。测量癫痫发作中NOX2和MDA活性的增加。此外,体视学分析显示PTZ点燃组的神经元丢失增加.qRT-PCR检测显示CHOP的相对mRNA水平。因此，TUDCA和4-PBA处理抑制了ATF4，ATF6，Cleaved-Caspase3，Kaspase12，NOX2，MDA的表达，和CHOP在TUDCA+PTZ和4-PBA+PTZ组中。通过减少神经元丢失和变性，ER应激诱导的氧化应激和凋亡也在这些组中得到保留。我们的数据在分子上显示TUDCA和4-PBA治疗可以抑制癫痫发作中的内质网应激过程。
