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目的评价比较N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体拮抗剂地佐环平(dizocilpine,MK-801)及作用于γ-氨基丁酸(γ-aminobutyric acid,GABA)系统药物———地西泮(diazepam,DZP)对四次甲基二砜四胺(tetramine,TET)所致难治性癫痫(refractory epilepsy,RE)的治疗效果,探讨其作用机制。方法在大鼠上建立TET所致RE模型,以动物行为学、EEG及脑病理学检测结果为评价指标,观察MK-801(3,5 mg/kg)及DZP(10,20 mg/kg)经腹腔注射给药对TET所致RE及由此引发脑损伤的抑制作用;采用实时定量PCR及Western印迹法,观察MK-801(5 mg/kg)及DZP(20 mg/kg)给药后对RE动物皮质NR2A/2B mRNA及蛋白表达的影响。结果 MK-801(3,5 mg/kg)均可有效抑制RE及由此引发的脑损伤,显著提升24 h存活率,其作用明显优于DZP;MK-801(5 mg/kg)可显著下调皮质NMDA受体2A/2B mRNA及蛋白表达,但DZP(20 mg/kg)无类似作用。结论 MK-801可显著抑制TET所致RE及由此引发的脑损伤,其作用可能与其对NMDA受体亚单位NR2A/2B的下调作用有关。
Objective To compare the effects of dizocilpine (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, and γ- Therapeutic effect of diazepam (DZP), a systemic drug, on refractory epilepsy (RE) induced by tetramine (TET) Its mechanism of action. Methods The RE model induced by TET was established in rats. The animal models of behavioral, EEG and brain pathology were used to evaluate the effects of MK-801 (3,5 mg / kg) and DZP (10,20 mg / kg) Intraperitoneal injection of TET-induced RE and the resulting brain damage caused by inhibition; real-time quantitative PCR and Western blotting to observe the MK-801 (5 mg / kg) and DZP (20 mg / kg) RE animal cortex NR2A / 2B mRNA and protein expression. Results Both MK-801 (3,5 mg / kg) and MK-801 (5 mg / kg) could effectively inhibit the RE and the brain damage induced thereby, and significantly improve the survival rate at 24 h. Downregulation of cortical NMDA receptor 2A / 2B mRNA and protein expression, but no similar effect of DZP (20 mg / kg). Conclusion MK-801 can significantly inhibit RE induced by TET and brain injury induced by TET, which may be related to its downregulation of NMDA receptor subunit NR2A / 2B.