Q808抗鼠最大电休克发作癫痫活性及其作用机制  

Study on the epileptic activity of Q808 against maximum electroconvulsive seizures and its mechanism of action

作　　者：王清[1] 李响 张殿文[1] 吴迪[1] 刘宁[1] 李伟[1] WANG Qing;LI Xiang;ZHANG Dian-Wen(Jilin Academy of Traditional Chinese Medicine,Changchun 130012,Jilin,China)

机构地区：[1]吉林省中医药科学院,吉林长春130012 [2]吉林大学基础医学院

出　　处：《中国老年学杂志》2021年第3期567-571,共5页Chinese Journal of Gerontology

基　　金：国家十二五“重大新药创制”科技重大专项(2011ZX09102-003);吉林省重大科技攻关项目(原“双十工程”重大科技攻关项目)(20170201003YY);吉林省科技支撑计划重大专项(20116039)。

摘　　要：目的观察Q808抗鼠癫痫活性及其作用机制。方法选取合格大鼠70只随机等分为7组,分别为模型对照组、托吡酯片20 mg/kg、丙戊酸钠100 mg/kg、苯妥英钠35 mg/kg、Q808高剂量60 mg/kg、Q808中剂量30 mg/kg、Q808低剂量15 mg/kg。灌胃给药1次,体积均为20 ml/kg,模型对照组给予同体积0.5%羧甲基纤维素钠(CMC-Na)。大鼠于给药后1、2、4、6、8、10、12 h各刺激1次。合格小鼠70只随机等分为7组,分别为模型对照组、托吡酯片25 mg/kg、苯妥英钠40 mg/kg、丙戊酸钠150 mg/kg、Q808高剂量80 mg/kg、Q808中剂量40 mg/kg、Q808低剂量20 mg/kg。灌胃给药1次,体积均为20 ml/kg,模型对照组给予同体积0.5%CMC-Na。小鼠于给药后1、2、4、6、8、10、12、24 h各刺激1次。大鼠于给药后1、2、4、6、8、10、12 h各刺激1次。以出现后肢强直性惊厥为观察指标,计算惊厥率。取雄性大鼠15只,分为两组,自发性兴奋性突触后电流(sEPSC)组6只,抑制性突触白电位(sIPSC)组9只。采用大、小鼠最大电休克发作(MES)癫痫模型和戊四唑、3-巯基丙酸诱发小鼠惊厥,观察其抗癫痫活性;采用高效液相色谱(HPLC)法分析大脑不同区域神经递质含量、采用膜片钳技术观察海马脑片CA1区椎体细胞和原代培养神经元上脑内γ氨基丁酯(GABA)电流,探讨其作用机制。结果灌胃给予大鼠60 mg/kg、小鼠80、40 mg/kg Q808后1 h即具有明显的抗MES作用,可持续作用12 h,且无种属差异;同时Q808能明显延长小鼠化学物质诱发惊厥模型的惊厥潜伏期、降低强直率、死亡率及发作级别。HPLC分析表明灌胃大鼠Q80860、30 mg/kg提高了海马GABA含量,降低了丘脑谷氨酸及谷氨酰胺含量,但对皮层神经递质没有明显作用。脑片电生理研究表明,Q808能增强海马脑片CA1区椎体细胞sIPSC频率,而对sIPSC幅值、sEPSC频率及幅值和原代培养神经元上GABA受体介导的电流没有明显影响,提示Q808可能通过提高突触间Objective To observe the anti-epileptic activity of Q808 and its mechanism of action.Methods Rats were stimulated once at 1,2,4,6,8,10,12 h after administration.Seventy qualified rats were randomly divided into 7 groups,which were model control,topiramate tablet 20 mg/kg,valproate 100 mg/kg,phenytoin 35 mg/kg,Q808 high dose 60 mg/kg,Q808 medium dose 30 mg/kg,and Q80815 mg/kg groups.Intragastric administration was performed once,with the volume of 20 ml/kg.The model control group was given 0.5%CMC-Na of the same volume.Mice were stimulated once at 1,2,4,6,8,10,12,24 h after administration.Rats were stimulated once at 1,2,4,6,8,10,12 h after administration.The occurrence of ankylosing convulsion was used as the index to calculate the convulsion rate.15 male rats were divided into 2 groups,6 in the spontaneous excitatory postsynaptic current(sEPSC)group and 9 in the inhibitory postsynaptic current(sIPSC)group.Rats and mouse models of MES were used,and pentylenetetrazol and 3-mercaptopropionic acid were used to induce convulsions in mice to observe their anti-epileptic activity.High performance liquid chromatography(HPLC)was used to analyze the neurotransmitter content in different areas of the brain,and the patch clamp technique was used to observe the GABA current in the vertebral cells of the CA1 area of the hippocampal slices and the upper brain of the primary cultured neurons to explore its mechanism of action.Results After intragastric administration of 60 mg/kg Q808 to mice,80,40 mg/kg Q808 to rats,Q808 had obvious anti-MES effect within 1 h,and it could last for 12 h without species difference.Q808 could significantly prolong the seizure latency of the chemical-induced convulsion model in mice,reduce the rate of rigidity,mortality and seizure level.HPLC analysis showed that 60,30 mg/kg Q808 increased hippocampal GABA content,decreased thalamic glutamate and glutamine content,but had no obvious effect on cortical neurotransmitters.Electrophysiological studies of brain slices showed that Q808 could enhance the

关 键 词：Q808 抗癫痫活性 最大电休克发作 

分 类 号：R749.17[医药卫生—神经病学与精神病学]