Study On Anti-epileptic Effect Of Novel Kv7 Potassium Channel Opener SCR

Object: Pentylenetetrazole(PTZ)kindling model of rats was established to study the anti-epileptic effects of the novel Kv7 potassium channel openers SCR-2682,SCR-2692 and their effects on electroencephalogram(EEG)and learning and memory abilities of PTZ-induced rats,which provide experimental evidence for the development of new anti-epileptic drugs.Methods: 1.Wistar female rats were injected intraperitoneally(i.p.)with a subconvulsant dose of PTZ(35 mg/kg)every other day to establish PTZ kindling model.The seizure behavior of rats was observed according to Ono criterion.2.Healthy rats were randomly divided into solvent control group,SCR-2682(0.4 mg/kg)group and SCR-2692(1.4 mg/kg)group.The drugs were treated once a day for 7 days.PTZ was injected intraperitoneally every other day.The effects of SCR-2682 and SCR-2692 on the development of PTZ kindling were observed.3.PTZ-kindled rats were randomly divided into solvent control group,retigabine(RTG,7.0 mg/kg)group,SCR-2682(0.2,0.4,0.8,1.2,1.6 mg/kg)group and SCR-2692(0.7,1.4,2.8,4.2,5.6 mg/kg)group.After treated with i.p.solvent,RTG,SCR-2682 and SCR-2692,i.p.PTZ induced seizures.The effects of SCR-2682 and SCR-2692 on PTZ-induced seizures were observed.4.Rats were randomly divided into normal control group,solvent control group,RTG(7.0 mg/kg)group,SCR-2682(1.6 mg/kg)group and SCR-2692(5.6 mg/kg)group.The BW-200 physiological wireless telemetry system was used to record and analyze the electroencephalogram of rats,and the effects of SCR-2682 and SCR-2692 on electroencephalogram of PTZ-kindled rats were detected.5.Rats were randomly divided into normal control group,solvent control group,RTG(7.0 mg/kg)group,SCR-2682(0.2,0.4,0.8,1.2,1.6 mg/kg)group and SCR-2692(0.7,1.4,2.8,4.2,and 5.6 mg/kg)group.The Morris water maze test was used to record the rats' escape latency and the times of across the original platform region within 60 s.The effects of SCR-2682 and SCR-2692 on the learning and memory abilities of PTZ-kindled rats were observed.6.PTZ-kindled rats were randomly divided into solvent control group,RTG(7 mg/kg)group,SCR-2682(1.6 mg/kg)group and SCR-2692(5.6 mg/kg)group.Treated with i.p.solvent,RTG,SCR-2682 and SCR-2692 daily for 7 days.After the last treatment,hippocampal tissue was isolated and Western Blot was used to detect the changes of KCNQ2 protein expression level in each group.Results: 1.PTZ kindling model was established successfully.In the solvent control group,the Ono's stage V-VI seizure was detected after 6.2 ± 3.1 times of i.p.PTZ.The Ono's stage V-VI seizure of SCR-2682(0.4 mg/kg)group and SCR-2692(1.4 mg/kg)group was detected after 15.4 ± 3.6,13.5 ± 3.0 times i.p.PTZ.SCR-2682 and SCR-2692 could retarded the development of PTZ kindling significantly.2.SCR-2682(0.4-1.6 mg/kg)and SCR-2692(1.4-5.6 mg/kg)could inhibit PTZ kindling seizure in rats and reduce the Ono's stage of seizure in the dose-dependent manner.3.The EEG of PTZ-kindled rats was obviously abnormal with frequent spikes,high-frequency waves(?,?)were increased significantly and amplitude was increased.SCR-2682(1.6 mg/kg)and SCR-2692(5.6 mg/kg)could significantly improve abnormal EEG of PTZ-kindled rats.As the spikes decrease,the low-frequency waves(?,?)were increased significantly,and the high-frequency waves were decreased significantly.4.The escape latency of PTZ-kindled rats was prolonged significantly and the times of across the original platform area were significantly reduced.It suggested that the learning and memory abilities of PTZ-kindled rats were reduced.SCR-2682 and SCR-2692 significantly reduced the escape latency of PTZ-kindled rats and significantly increased the times of across the original platform area.SCR-2682 and SCR-2692 could improve the learning and memory abilities of PTZ-kindled rats.5.SCR-2682 and SCR-2692 had no effect on the expression level of KCNQ2 protein of PTZ-kindled rats.Conclusion:SCR could significantly inhibit the development of PTZ kindling and the PTZ kindling seizure.SCR could also improve abnormal EEG and learning and memory abilities of PTZ-kindled rats.The result suggest that the novel Kv7 potassium channel openers SCR-2682 and SCR-2692 may sever as new anti-epileptic drugs.