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

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Technical Report,15 May 2012,31 May 2015

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New York Medical College Valhalla United States

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We developed electrophysiological, two-photon laser scanning microscopic imaging and pharmacological tools to investigate the effects of levetiracetam, topiramate and carbamazepine on excitatory glutamatergic synaptic transmission and vesicular transmitter release at multiple synapses in in vitro brain slices from control and pilocarpine-treated epileptic rats and mice. We discovered that levetiracetam was more effective in reducing the frequency of excitatory synaptic transmission onto dentate granule cells in slices from chronically epileptic rats, while no significant effect was detected in the amplitude of mEPSCs, indicating a presynaptic site of action without postsynaptic effects on AMPA glutamate receptors. These data correlated well with findings in imaging experiments that LEV was more effective in suppressing the enhanced vesicular release of glutamate from mossy fiber terminals in field CA3 of epileptic mice, compared to none pileptic control animals. These data indicate that presynaptically acting drugs such as levetiracetam may become a key piece in the arsenal of antiepileptic drugs in mesial temporal lobe epilepsy, and highlight the need for preventing the down regulation of sensitivity tolevetiracetam observed with chronic administration in some patients. Thus, screening for a presynaptic site of action and assessment of chronic tachyphylaxis of presynaptic actions will be important to the discovery of novel and effective antiepileptic drugs.

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  • Medicine and Medical Research
  • Pharmacology

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