Antiepileptic Effect Of The Novel Kv7 Channel Opener Scr2682 In Kainic Acid Induced Seizures

Epilepsy is a common chronic neurological disorder.Among the patients with epilepsy,approximately 30-40% of them develop learning and memory impairments,especially in the patients with temporal lobe epilepsy(TLE).Pharmacotherapy has been a primary treatment for epilepsy.Unfortunately,between 25% and 40% of patients with epilepsy develop resistance to existing antiepileptic drugs(AEDs).The resistance rate in TLE is even higher,at 75%.These patients are often treated with multiple AEDs,either alone or in combination,and still fail to effectively control their seizures.Therefore,it is necessary to develop novel therapeutic agents to meet a wide range of medical needs by mitigating recurrent seizures and improving cognitive deficits.An imbalance between excitatory and inhibitory activity of neurons can lead to frequent discharges,which can trigger seizures.Voltage-gated Kv7/KCNQ/M potassium channels play important roles in the regulation of membrane potential and neuronal excitability.Activation of Kv7 channels can inhibit neuronal hyperexcitability,which has development potential in the treatment of neuronal hyperexcitability diseases such as epilepsy.Retigabine(RTG)is the first marketed Kv7 channel opener,for the adjunctive treat ment for partial-onset seizures in adults,but was discontinued due to severe adverse effects.Therefore,new antiepileptic drugs targeting Kv7 channels are urgently needed.Our previous study has shown that the novel Kv7 channel opener SCR2682 selectively activates neuronal Kv7 channels with a stronger activation ability than RTG and better safety.Therefore,SCR2682 is a potential Kv7 channel opener.Objective: The chronic model of spontaneous recurrent seizures,induced by the glutamate receptor agonist kainic acid(KA),is considered the most classical animal model to simulate TLE.In this study,we evaluated antiepileptic effects and attenuation of cognitive deficits by a novel Kv7/KCNQ/M channel opener SCR2682 in KA-induced acute or chronic spontaneous recurrent seizures of rats.It provides the experimental basis for the development of a novel Kv7 channel opener SCR2682.Methods:1.KA was injected into the lateral ventricle of conscious rats to induced acute seizures,and the antiepileptic effect of SCR2682 was evaluated.2.KA was injected into the lateral ventricle of anesthetized rats.Two to three weeks later,the rats developed spontaneous recurrent seizures,and the antiepileptic effect of SCR2682 was evaluated.3.The electroencephalogram(EEG)was recorded and analyzed with electrophysiological system to evaluate the effect of SCR2682 in KA-induced acute and chronic spontaneous recurrent seizures.4.Y maze test was performed to evaluate the effect of SCR2682 on the spatial working memory in KA-induced chronic spontaneous recurrent seizures.5.Nissl staining and immunofluorescence of neuronal nuclei(Neu N)were performed to observe the effect of SCR2682 on hippocampal neurons in KA-induced chronic spontaneous recurrent seizures.Results:1.In KA-induced acute seizures,SCR2682(0.4,0.8,1.6 mg/kg,i.p.)could decrease the Racine score of seizures in a dose-dependent manner.2.In KA-induced chronic spontaneous recurrent seizures,SCR2682(0.4,0.8,1.6 mg/kg,i.p.)could reduce the average number of seizures per day and the duration of seizures per day in dose-dependent manner.3.In the EEG recording of KA-induced seizure model,SCR2682(0.4,0.8,1.6 mg/kg,i.p.)significantly reduced the number of spikes in acute and chronic seizure model,decreased the power spectral density of EEG in acute seizures and the total time of epileptiform discharge in chronic spontaneous recurrent seizures.4.In the Y maze test of KA-induced chronic seizure model,the movement time of rats in the KA + Veh group showed a significant decrease in the novel arm as compared with the control group.After 14 days of treatment with SCR2682(1.6 mg/kg,i.p.),the movement time of rats in the novel arm was significantly increased,and the spatial working memory ability was significantly improved.5.Nissl staining and immunofluorescence of neuronal nuclei showed that there was an extensive loss of neurons in the hippocampal of rats in the KA group as compared with the control group.SCR2682(1.6 mg/kg,i.p.)could attenuate hippocampal neuronal loss and effectively prevent neurodegeneration in KA-induced chronic spontaneous recurrent seizures.Conclusions:1.In KA-induced acute and chronic spontaneous recurrent seizures,SCR2682 can effectively inhibit seizures in rats.2.In KA-induced chronic spontaneous recurrent seizures,spontaneous recurrent seizures could induce cognitive dysfunction and damage of hippocampal CA3 neurons in rats,and SCR2682 could significantly improve cognitive dysfunction and protect hippocampal neurons.