Increase in drug-induced seizure susceptibility of transgenic mice overexpressing GABA transporter-1  

过量表达GABA转运蛋白-1的转基因小鼠对药物诱发癫痫易感(英文)

作　　者：赵文娟[1] 马映华[1] 费俭[1] 梅镇彤[2] 郭礼和[1] 

机构地区：[1]中国科学院上海生命科学研究院生物化学与细胞生物学研究所 [2]中国科学院上海生理学研究所

出　　处：《Acta Pharmacologica Sinica》2003年第10期991-995,1061,共6页中国药理学报（英文版）

摘　　要：AIM: The changes of seizure susceptibility of transgenic mice overexpressing GABA transporter-1(GAT-1) were studied to clarify the possible role of GABAergic transmission in epileptogenesis. METHODS: Seizures were induced by intraperitoneal administration of pentylenetetrazol(PTZ), picrotoxin(PIC), or kainic acid(KA) respectively. The anticonvulsant effect of ethyl nipecotate was tested by its intraperitoneal injection 15 min before the administration of the epileptogenic agents. RESULTS: The percentages of occurrence of clonic seizures induced by PTZ 45 mg/kg, PIC 2.5 mg/kg, or KA 20 mg/kg in GAT-1 transgenic mice were 88.9%, 100%, and 83.3% respectively, whereas those in control C57BL/6J mice were 42.9%, 57.1%, and 33.3%. The percentages of occurrence of tonic seizures induced by PTZ 45 mg/kg, PIC 2.5 mg/kg, or KA 20 mg/kg in transgenic mice were 88.9%, 100%, and 83.3% respectively, and whereas those in control mice were 28.6%, 42.9%, and 16.7%. The latencies of both clonic and tonic seizures onset in transgenic mice were markedly shortened compared with those in control animals. The results indicated that GAT-1 transgenic mice showed increased susceptibility to seizures induced by the anti-GABAergic convulsive drugs(PTZ, PIC), as well as glutamic receptor agonist(KA). Ethyl nipecotate, inhibitor of GAT-1, inhibited PTZ-induced seizures in both GAT-1 transgenic and C57BL/6J mice. The incidence of seizures was decreased after the application of ethyl nipecotate, and the latencies to the onset of clonic or tonic seizures were also prolonged. CONCLUSION: The increase in seizure susceptibility of transgenic mice over-expressing GAT-1 is an evidence for involvement of GABAergic transmission in epileptogenesis, and this transgenic mouse might be a useful animal model for study on the role of GABAergic transmission in epileptogenesis.目的:应用过量表达GABA转运蛋白Ⅰ(GAT-1)的转基因小鼠研究GAT-1在癫痫发生中的作用。方法:采用腹腔注射戊四唑(PTZ),印防己毒素(PIC)或红藻氨酸(KA)诱导的癫痫发作为模型,比较GAT-1转基因小鼠和C57BL/6J对照小鼠阵挛性发作和强直性痉挛发生的百分率及潜伏期.结果:GAT-1转基因小鼠不但对不同剂量GABA_A受体抑制剂PTZ,PIC,也对谷氨酸受体激动剂KA诱导的癫痫易感.GAT-1抑制剂ethyl nipecotate可明显减轻PTZ诱导的癫痫发作。结论:GAT-1转基因小鼠对癫痫易感证明GABA系统参与了癫痫发生,并且该转基因小鼠模型可作为研究癫痫发生的有用动物模型。

关 键 词：neutrotransmitter transporter carrier proteins seizures GABA PENTYLENETETRAZOL PICROTOXIN kainic acid ethyl nipecotate transgenic mice 

分 类 号：R742.1[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]