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New Treatments for Drug-Resistant Epilepsy that Target Presynaptic Transmitter Release

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Technical Report,15 Apr 2014,14 Apr 2015

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University of Texas at Brownsville Brownsville United States

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We developed electrophysiological and pharmacological studies to investigate the effects of levetiracetam, topiramate and carbamazepine in excitatory glutamatergic synaptic transmission onto granule cells in the dentate gyrus from slices of control and pilocarpine-treated epileptic rats and mice. We discover a novel presynaptic action of topiramate reducing the frequency of mEPSC in a dose-dependent manner while the inhibitory action on mEPSC amplitude was also present in both control and epileptic slices. Hence, our findings indicate that topiramate exert, at least in part a presynaptic action inhibiting the release of glutamate. We detected that levetiracetam inhibits the spontaneous glutamate release mEPSC frequency in control and epileptic rats and mice. In addition, levetiracetam was more effective in reducing excitatory synaptic transmission onto dentate granule cells in slices from chronically epileptic rats while no effect was detected on the amplitude of mEPSC indicating no action of post-synaptic AMPA receptors. We also detected that LEV increase the GABAergic inhibitory transmission onto dentate granule cells by increasing the frequency of mIPSCs. These data indicate that presynaptically acting drugs as levetiracetam may become a key piece in the arsenal of antiepileptic drugs in mesial temporal lobe epilepsy. Thereby, screening for a presynaptic action site may be part of the strategy to discover novel and effective antiepileptic drugs.

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