Effects Of KCNQ Potassium Channel Opener On Rat Hippocampus Iring In Vivo

BackgroundEpilepsy, one of the most common neurological disorders, is defined by suddenrecurrent seizures that are caused by an electrical hyperexcitability in the centralnervous system and is a serious threat to people’s life and health. An epileptic seizureis the result of disorders of the brain. So far, the clinical treatment of epilepsy relieson drug therapy, but patients sustain suffering from epilepsy or severe side effectsdespite the treatment of daily dosage of antiepileptic drug.Retigabine (RTG), a first-in-class antiepileptic drug has been authorized by FDAin2011, with a mechanism of activation of KCNQ voltage-gated potassium channel.The agonists of potassium channels play an important role in maintenance of cellexcitability and in transmission of information within the nervous system. Theunderstanding of the mechanism of antiepileptic drug has been intensely studied.However, most of previous mechanism studies on RTG rely on electrophysiologicalrecording in vitro. Effects of RTG on specific nuclear groups in vivo are not wellunderstood.ObjectiveEstablish the stable free animal electrical signal acquisition system and studyeffects of RTG on the firing of hippocampal neurons in free moving rats. Our studywill provide insight into the antiepilepsy mechanism of KCNQ agonist RTG.MethodsAdult male Sprague-Dawley rats are weighting250-350g. The rats areanesthetized and stereotaxically implanted with2*4arrays electrode. The rats arehoused into a regulated environment with food available ad libitum. Seven days ofrecovery from surgery, the rats are put into adjacent box that can make the rats movefreely. The discharge of neurons in the brain can be stable recording and cansustainable existence one or two weeks. The electrode is connected to the recordingapparatus via a headstage. Hippocampal activities are transmitted via the connecting cable to a multichannel acquisition processor system. The dates are acquired withpreamplifier and transformed to computer.The antiepileptic and other drugs are administration by intraperitoneal (i.p.)injection. The effects of RTG on firing frequency of hippocampal neurons areanalysis. Experiment stable record electrical signals10min, then RTG isadministration in dose of15mg/kg. The stability and gathering electrical signals for360min are recording. Next, to study effect of RTG15mg/kg on the dischargesinduced by4-AP5mg/kg and XE99110mg/kg. With former electrical signalacquisition method, the activities of neurons are stable record10min after4-AP istreatment with5mg/kg and stable record120min after XE991is treatment with10mg/kg. Then RTG is administration in dose of15mg/kg. The stability and gatheringelectrical signals for360min are recording. All signals are stored in the computerusing the offline sorter for off-line analysis.ResultsA stable free animal electrical signal acquisition system is successfullyestablished. Using this system, the hippocampal neurons are firstly sorted. Theneffects RTG effects on the hippocampal neurons are examined. We found that RTGeffectively suppresses the firing rates of both pyramidal neurons and interneurons at15mg/kg concentration (i.p.). We demonstrate that4-AP induced hippocampalepileptiform activity in vivo and seizing behavior, which are attenuated with RTG. Inaddition, under the same concentration, RTG effectively converts thehyperexcitability of hippocampal neurons induced by XE991, a blocker of KCNQpotassium channel, which is consistent to its potentiation activity on KCNQpotassium channel in vitro.ConclusionsUsing the multi-channel recording technology, we first time investigate theeffects of RTG, a KCNQ potassium channel opener, on rat hippocampus firing in thecurrent study. Our study indicates that suppression of firing of hippocampal neuronscontributes to the antiepileptic effects of the drug, which provides insight into themechanism of RTG treating epilepsy.