Studies Of The Antiepileptic Effect And Mechanism Of Natural Small Molecule DV21

Epilepsy is one of the most common neurological disorders characterized by recurring and unprovoked seizures and the mechanism is still not very clear.More than approximately 65 million people worldwide have been affected;there are nearly 40,000 new patients only one year,and 150,000 new cases are diagnosed every year in the United Stated alone.Currently,the most common treatment for epilepsy is the administration of antiepileptic drugs(AEDs),and the target points concentrated in sodium ion channel,NMDA receptor,benzodiazepines receptors,and so on.Despite the current availability of more than 15 AEDs,a third of.patients remain refractory to available drugs.Only about 1%of patients could treat epilepsy with surgical.As a consequence,it is necessary and urgent to clarify the pathogenesis of epilepsy and find newer and more effective drugs.Traditional Chinese Medicine(TCM)and ethnopharmacology have been important resources of novel active natural products that could serve as leads and scaffolds for development into efficacious drugs that are needed.In southwestern China,some plants of the Asclepiadaceae family have been used to treat epilepsy by local residents.So can we find a natural product which can treat epilepsy?We identified an activated small natural molecule,termed DV21.And we found that the antiepileptic effect of DV21 is stronger than clinical 4 drugs,it displayed significant antiepileptic effect in 1?M.We also tested the antiepileptic effect of DV21 on C57BL/6 wide-type mice as well as by electrophsiological methods to explore the antiepileptic mechanism of DV21.We used three drugs to induce acute epilepsy models on C57BL/6 mice(PTZ,KA,PILO),and injected different concentrations of DV21 on experiment groups by intraperitoneal as well as injected vehicle on control groups.With the concentrations of DV21 increased,the PTZ and KA groups showed significant decrease on seizure incidence and severity,but the Pilocarpine group showed that more antiepileptic activity of DV21 on the low dose group by analyzed the EEG,EMG and video.We also gave DV21 by intraventricular adminstrtion on three acute epilepsy models to test the antiepileptic activity,and compared with two clinical drugs.We found that the antiepileptic activity of DV21 is closer to retigabine which suggest the mechanism is similar to retigabine.To investigate the mechanism of DV21,we did the electrophysiology experiments to explore it.The results revealed that the number of action potentials was decrease when we add DV21 in the ACSF and we also found DV21 directly change the intrinsic properties of pyramidal neurons.We also found that the antiepileptic effect of DV21 was mediated through reductions in the excitability of cortical pyramidal neurons by increasing M-currents.Overall,we found a new natural product that could decrease the severity of epilepsy on zabrafish and mice models,and we identified M-currents as a molecular target of DV21 in the regulation of cortical pyramidal neuron excitability.Our findings suggest that DV21 might be a new anticonvulsant drug to treat epilepsy.