Screening of a KCNQ potassium channel opener and observation of its antiepileptic activity
- VernacularTitle:KCNQ钾离子通道开放剂的筛选及抗癫痫活性观察
- Author:
Jia LI
1
;
Yuan WANG
;
Chao SONG
;
Qing-Zhong JIA
;
Jin-Long QI
Author Information
- Keywords: seizure; KCNQ opener; high throughput screening; pentylenetetrazole; electroencephalogram; general pharmacology
- From: Chinese Pharmacological Bulletin 2024;40(9):1744-1752
- CountryChina
- Language:Chinese
- Abstract: Aim To screen out the KCNQ channel o-peners and evaluate the antiepileptic activity.Methods The high throughput screening(HTS)method of Rb+efflux assay was used to identify the active com-pound of KCNQ opener;the preferred compound QO-7 2 was selected to test the pharmacological action in multiple animal models;through the analysis of behav-ioral and EEG,combined with the observation of gener-al pharmacological experiments,the efficacy and safety of the drug were preliminarily evaluated,and the mech-anism 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 differ-ent 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 signif-icantly extended(P＜0.01).In chronic epilepsy model,the seizure ranks and duration significantly de-creased 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 o-pening KCNQ channels,but also to increasing the con-tent of inhibitory neurotransmitter GABA in brain.
