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

Anti-epileptic effect of dizocilpine on refractory epilepsy induced by tetramine in rats

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 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.