地佐环平对四次甲基二砜四胺诱发大鼠难治性癫痫的抑制作用

摘要

Objective To evaluate and compare the anti-epileptic effects of N-methyl -D-aspartate ( NMDA) receptor antagonists dizocilpine ( MK-801 ) and diazepam ( DZP) which acts on γ-aminobutyric acid ( GABA) system on tetramine ( TET) -induced refractory epilepsy ( RE ) in rats. Methods Upon the establishment of TET induced RE in rats , the anti -epileptic effect and neuroprotection of MK-801 (3 and 5 mg/kg)and DZP(10 and 20 mg/kg)on TET induced RE and brain injury were examined by behavior , EEG and HE-staining. Using real-time quantitative polymerase chain reaction ( RT-PCR) and Western blotting, the effect of MK-801 (5 mg/kg)and DZP(20 mg/kg)on the expression of NR2A/2B mRNA and corresponding proteins was tested. Results MK-801 (3,5 mg/kg) showed better anti-epileptic and neuroprotective effects on TET-induced RE and brain injury than DZP. Furthermore, the mRNA and corresponding proteins of NR2A/2B were down regulated obviously in MK-801 (5 mg/kg) treatment groups while the expression of NR2A/2B remained unchanged in DZP(20 mg/kg) treatment group. Conclusion MK-801 can effectively inhibit the RE and brain injury caused by TET; its inhibitive effects may be related to the down-regulating effects on the expression of NR2A/2B receptor.%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.