The Antiepileptic Effects Of Transcutaneous Auricular Vagus Nerve Stimulation In Drug Refractory Epileptic Rats And The Discussion Of Its Mechanisms

Objective To study the antiepileptic effects of transcutaneous auricular vagus nerve stimulation in drug refractory epileptic rats and discuss its mechanisms.Methods Lithium chloride-Pilocarpine was used to establish rat models of spontaneous recurrent temporal lobe epilepsy,and then the drug refractory epileptic rats were screened out by sodium phenobarbital.In order to study the difference between the therapeutic effects of transcutaneous auricular vagus nerve stimulation and vagus nerve stimulation on seizures in drug refractory epileptic rat models,the frequency of seizures was compared and the pathological changes and apoptosis of hippocampal neurons were studied by Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling(TUNEL)technology after the stimulation of 4 weeks.With the purpose of exploring the mechanisms of transcutaneous auricular vagus nerve stimulation,the levels of Bcl-2,Bax and the activated caspase-3,which are apoptosis-related proteins,in hippocampus in each group were detected by western blot.Results The models of the drug refractory epileptic rats were successfully established.The RE+ ta-VNS and RE+ VNS groups had a 72.0% and 80.7% decrease in the average frequency of seizures,and there were statistical differences between the two groups and the RE group(P<0.05).But there was no statistical difference between the RE+ ta-VNS and RE+ VNS groups(P=0.12).Nissl and TUNEL staining showed that the neuronal injury and apoptosis in hippocamps of the RE group were more serious than those of the blank control group.There was no statistical difference between the RE+ ta-VNS and RE+ VNS groups whose neuronal injury and apoptosis in hippocamps were lighter than those of RE group.Compared with RE group,the decreased level of Bcl-2 protein induced by seizures increased obviously in RE+ ta-VNS group(P<0.05),while the increased levels of Bax and activated caspase-3 proteins were reserved in RE+ ta-VNS group(P<0.05).Conclusions It is a reliable method to establish drug refractory epileptic rat models by igniting with lithium chloride-Pilocarpine and screened out with sodium phenobarbital.Both ta-VNS and VNS not only can reduce the frequency of seizures significantly but also can protect hippocampal neurons effectively in drug refractory epileptic rats.The effects of ta-VNS are near to those of VNS,but ta-VNS has the advantages of non-invasion,less side effects and so on.The mitochondrial apoptosis pathway is suppressed by up-regulating the ratio of Bcl-2/Bax and inhibiting the activation of caspase-3,which maybe one of the antiepileptic mechanisms of ta-VNS.