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目的探讨2-脱氧葡萄糖诱导内质网应激预适应对癫持续状态大鼠海马神经元的保护作用及其可能机制。方法采用2-脱氧葡萄糖连续腹腔注射诱导内质网应激,并在此基础上制备氯化锂-匹罗卡品癫持续状态大鼠模型。Nissl染色观察癫持续状态后海马神经元损伤情况、计数海马CA1和CA3区存活神经元数目;免疫组织化学检测海马CA3区内质网应激标志物葡萄糖调节蛋白78(GRP78)和X盒结合蛋白1(XBP-1)表达变化。结果与癫持续状态组相比,癫持续状态后第7天时内质网应激预适应组大鼠海马存活神经元数目增加,以CA1区显著(t=5.353,P=0.000)。癫持续状态组大鼠发作后6 h,海马CA3区GRP78和XBP-1表达水平升高且高于对照组(均P=0.000),于发作第2天达峰值水平(均P=0.000);内质网应激预适应组大鼠发作前海马CA3区GRP78和XBP-1表达即高于对照组(均P=0.000),GRP78在发作后24 h和2 d时维持在峰值水平(均P=0.000),XBP-1在发作后24 h达峰值水平(P=0.000);内质网应激预适应组大鼠海马CA3区GRP78和XBP-1表达在癫持续状态前,以及癫持续状态后6、12、24 h均高于癫持续状态组(均P=0.000),至第2和7天时与癫持续状态组之间差异无统计学意义(P>0.05)。结论经2-脱氧葡萄糖诱导的内质网应激预适应对癫持续状态大鼠海马神经元具有保护作用,而XBP-1-GRP78信号转导通路的活化可能是其机制之一。
Objective To investigate the protective effect of 2-deoxyglucose-induced endoplasmic reticulum (ER) preconditioning on hippocampal neurons in epilepticus and its possible mechanism. Methods Endoplasmic reticulum stress was induced by continuous intraperitoneal injection of 2-deoxyglucose, and on the basis of this, a rat model of epilepticus induced by lithium-pilocarpine was established. Nissl staining was used to observe the damage of hippocampal neurons after the status epilepticus, and the number of neurons in hippocampal CA1 and CA3 were counted. The expression of endoplasmic reticulum stress marker glucose regulatory protein 78 (GRP78) and X box in hippocampal CA3 region were detected by immunohistochemistry Protein 1 (XBP-1) expression changes. Results Compared with the status epilepticus group, the number of hippocampal neurons in the endoplasmic reticulum stress preconditioning group increased on the 7th day after the epilepticus persistence, and the CA1 region was significant (t = 5.353, P = 0.000). The expression level of GRP78 and XBP-1 in hippocampal CA3 area was significantly higher than that in control group (all P = 0.000) at 6 h after epileptic seizure, and peaked at the second day of seizure (both P = 0.000) ; The expression of GRP78 and XBP-1 in hippocampal CA3 area before ER stress preconditioning group was higher than that in control group (all P = 0.000), while GRP78 peaked at 24 and 2 d (P = 0.000); XBP-1 peaked at 24 h after onset (P = 0.000); the expression of GRP78 and XBP-1 in hippocampal CA3 area of ER stress preconditioning group was significantly higher than that before epileptic continuation There was no significant difference between the status group and the status epilepticus on the 2nd and 7th days (P> 0.05) at 6, 12 and 24 hours after the continuous status. Conclusion Preconditioning of endoplasmic reticulum stress induced by 2-deoxyglucose can protect the hippocampal neurons of epileptic rats. Activation of XBP-1-GRP78 signal transduction pathway may be one of the mechanisms.