KCNQ钾离子通道开放剂的筛选及抗癫痫活性观察  

Screening of a KCNQ potassium channel opener and observation of its antiepileptic activity

作　　者：李佳[1,2] 王远[1,3] 宋超 贾庆忠[1] 祁金龙[1] LI Jia;WANG Yuan;SONG Chao;JIA Qing-zhong;QI Jin-long(Dept of Pharmacology,Key Laboratory of Vascular and Neurobiology of Ministry of Education,Key Laboratory of New drug Pharmacology and Toxicology of Hebei Province,Hebei Medical University,Shijiazhuang 050017,China;Dept of Outpatient,Hebei Medical University,Shijiazhuang 050017,China;Dept of Pharmacy,Hebei Provincial Hospital of Traditional Chinese Medicine,Shijiazhuang 050011,China)

机构地区：[1]河北医科大学药理学教研室,教育部血管与神经生物重点实验室,河北省新药药理毒理重点实验室,河北石家庄050017 [2]河北医科大学门诊部,河北石家庄050017 [3]河北省中医院药学部,河北石家庄050011

出　　处：《中国药理学通报》2024年第9期1744-1752,共9页Chinese Pharmacological Bulletin

基　　金：河北省中央引导地方科技发展基金项目(No 226Z2602G);河北省卫健委医学科学研究课题计划项目(No 20200035);河北省重点研发计划项目(No 21372601D);河北省生物医药联合基金培育项目(No H2022206201)。

摘　　要：目的筛选KCNQ通道开放活性化合物并进一步评价其抗癫痫作用。方法利用铷流出高通量筛选技术初筛,对优选化合物QO-72,复制多个动物模型,通过行为学以及脑电图(EEG)分析,结合一般药理学实验,对其有效性安全性进行初步评价,并探讨作用机制。结果得到3个系列活性化合物共51个。化合物QO-72在MES和PTZ急性实验中,灌胃和腹腔注射可明显提高抗惊厥保护率(P<0.05,0.01),延长癫痫大发作阈值(P<0.01)。在PTZ点燃慢性癫痫模型中,QO-72腹腔注射不同剂量均可降低癫痫发作等级(P<0.01),缩短癫痫发作持续时间(P<0.01),大剂量明显提高发作保护率(P<0.01);QO-72治疗组EEG癫痫波时程明显缩短、振幅明显降低、波功率谱密度明显下降(P<0.05,0.01)。QO-72灌胃给药治疗剂量16倍或腹腔注射8倍,对小鼠协调运动、自主活动、戊巴比妥钠协同睡眠无明显影响。QO-72给药组海马区脑脊液GABA含量可明显增加(P<0.01),Glu没有明显变化(P>0.05)。结论化合物QO-72在电刺激和化学诱导的急、慢性癫痫模型上,均表现出良好抗癫痫作用,其机制除开放KCNQ通道外,可能还与增加脑内抑制性神经递质GABA含量有关。Aim To screen out the KCNQ channel openers and evaluate the antiepileptic activity.Methods The high throughput screening(HTS)method of Rb+efflux assay was used to identify the active compound of KCNQ opener;the preferred compound QO-72 was selected to test the pharmacological action in multiple animal models;through the analysis of behavioral and EEG,combined with the observation of general pharmacological experiments,the efficacy and safety of the drug were preliminarily evaluated,and the mechanism was explored.Results By HTS we identified three series compounds with high activity,a total of 51 compounds.In the results,the QO-72 ig or ip in different doses showed significant anticonvulsant activity in the MES and PTZ induced acute epilepsy models,the anticonvulsant protection rate significantly increased(P<0.05,0.01)and the seizure threshold was significantly extended(P<0.01).In chronic epilepsy model,the seizure ranks and duration significantly decreased in the QO-72 treatment groups(P<0.01)and the antiepileptic protection rates significantly increased in the higher dose(P<0.01).Compared with PTZ group,the amplitude,seizure wave duration and power density of EEG were reduced significantly in QO-72 treatment groups(P<0.05,0.01).Besides,rotarod,spontaneous activity and cooperative sleep tests of mice by ig at 16 times,ip at 8 times of therapeutic dose had confirmed that the QO-72 had no central side effect.Further mechanism studies were performed on the QO-72 treated animals,the outcomes revealed that there was a significant elevation in GABA(P<0.01)in hippocampus,but there was no significant change in Glu(P>0.05).Conclusions The compound QO-72 shows significant antiepileptic activity in the MES and PTZ models;the mechanism is not only related to opening KCNQ channels,but also to increasing the content of inhibitory neurotransmitter GABA in brain.

关 键 词：癫痫 KCNQ开放剂 高通量筛选 戊四唑 脑电图 一般药理学 

分 类 号：R-332[医药卫生] R329.24R741.044R742.1R971.6