代谢型谷氨酸受体亚型5拮抗剂MPEP、亚型8兴奋剂S-DCPG联合用药在小鼠癫痫治疗中的作用

Anti-epilepsy activity of a mGluR5 antagonist, MPEP,linked with a mGluR8 agonist,S-DCPG, in Swiss mice

目的:观察2-甲基-6-苯基乙炔嘧啶(2-methyl-6-phenylethynyl-pyridine,MPEP)与S-二羧基苯基甘氨酸(S-3,4-Dicarboxyphenylglycine,S-DCPG)联合用药在毛果芸香碱诱导的癫痫小鼠动物模型中的抗抽搐及对大脑神经元的保护作用。方法:取5—6周龄瑞士雄性小鼠行颈静脉插管。插管后第3天腹腔注射毛果芸香碱诱导小鼠癫痫模型。待癫痫发作1h通过颈静脉插管给予四种不同剂量的MPEP+S-DCPG(100+100mg/kg、100+200mg/kg、200+100mg/kg、200+200mg/kg),观察其抗癫痫活性。给药后24h断头取脑行病理观察,并计算海马齿状回门区中间神经元的密度。结果:四种剂量组在癫痫发作后1h给药均有明显的抗抽搐活性,并随剂量的增加有增加的趋势,对海马齿状回门区中间神经元亦有一定的保护作用,虽然前两种剂量组与实验对照组比较P>0.05,但其神经元的密度明显高于实验对照组,后两种剂量组与实验对照组相比P<0.05。结论:MPEP+S-DCPG对毛果芸香碱诱导的癫痫小鼠模型有明显的抗抽搐活性,对海马齿状回门区中间神经元亦有明显保护作用,并在实验剂量范围内随着剂量的增加有明显的增加趋势。

Objective：To evaluate the anti-seizure and neuroproteetive effects of a metabotropic glutamate receptor （mGluR）5 antagonist, 2-methyl-6-（phenylethynyl）-pyriding （MPEP）,linked with a mGluR8 agonist, （S）-3,4- Diearboxyphenylglycine （S-DCPG）,after pilocarpine-induced status epilepticus in Swiss mice.Method：Male Swiss mice,about five to six weeks,were used.Cannulation was done through the jugular vein. After three days of cannulation,the mice were induced epileptic with pilocarpine,MPEP＋S-DCPG were injected through the polyethylene tube in different dosages （100＋100mg/kg, 100＋200mg/kg, 200＋100mg/kg,200＋200mg/kg） at 1 hour during status epilepticus, The behavioral changes of mice were observed,After 24 hours of drugs injection,the mice were killed, The number of neurons in the hilus of dentate gyros in the dorsal hippoeampus was counted.Result：MPEP＋S- DCPG at four kinds of dosages ~：ouht stop seizures at 1 hour during pilocarpine-indueed status epilepticus and exhibit more effective following the increase of the dosage, MPEP＋S-DCPG at 200＋100mg/kg and 200＋200mg/kg exhibited neuroproteetive effect in the hilus of the dentate gyros at 1 hour during pilocarpine-induced status epilepticus （P〈0.05）,At 100＋100mg/kg and 100＋200mg/kg, in spite of P〉0.05, MPEP＋S-DCPG seemed to have some neuroprotective effects, Conclusion：MPEP＋S-DCPG is effective in the prevention of seizures or neuronal death in the epilepsy model of piloearpine-induced Swiss mice through intravenous injection.