OBJECTIVE To explore the antiepileptic activity of QO-83,a novel KCNQ channel opener,by establishing and optimizing a 6 Hz corneal kinked model,and to provide a scientific basis for the application of QO-83 in drug-resistant epilepsy.METHODS The mice were divided into control group,model group,positive drug levetiracetam(100 mg·kg-1)group,control drug carbamazepine(50 mg·kg-1)group,and QO-83 low(2 mg·kg-1),medium(4 mg·kg-1),and high(6 mg·kg-1)dose groups.The 6 Hz kindled mice were established,and drugs was injected intraperitoneally.After 30 min,6 Hz corneal stimulation was applied again to observe its protective effect on the animal.And set up a series of behavioral experiments:tail suspension test,T-maze test,and new object recognition test,observe the immobility time,selection accuracy,and recognition index of mice respectively,to evaluate its impact on animal depressive tendencies and memory abilities.Immunofluorescence staining was performed on 6 Hz model mice to observe the expression changes of c-Fos protein and evaluate the protective effect of QO-83 on specific brain regions.Observe the expression changes of its target KCNQ2 protein and evaluate its impact on target protein expression.RESULTS The established model mice were not sensitive to the action of carbamazepine(50 mg·kg-1),but effective against levetiracetam(100 mg·kg-1).When given 2,4 and 6 mg·kg-1 QO-83,dose-dependent anti-epileptic effects can be observed,which significantly reduced the inci-dence and duration of seizures in ignited mice.The 4 mg·kg-1 of QO-83 can significantly reduce the immobility time of epileptic mice in tail suspension experiments,increase the accuracy of mice in T-maze test,and increase the recognition index(RI)of mice in new object recognition test.QO-83 can significantly downregulate the expression of c-fos in the hippocampus and piriform cortex of epileptic mice,and upregulate the expression of KCNQ2 protein in the CA3,DG regions and their surrounding fibers and PIR regions of late-stage model mice.CONCLUSION Compound QO-83 has good anti drug-resistant epilepsy activity,and its protective effect on epileptic animals is better than the positive drug levetiracetam.At the same time,it also has the effect of improving the behavior of epileptic animals,demonstrating the therapeutic potential for drug-resistant epilepsy.The mechanism of action may be related to upreg-ulating the expression of the target protein KCNQ2.
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