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

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Annual rept. 15 Apr 2011-14 Apr 2012

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In year 01, we completed the majority of our studies in Aim 1 and a portion of Aim 2. We found, in both rats and mice, that severe pilocarpine-induced seizures that result in long-term appearance of spontaneous epileptic seizures are associated with marked changes in the structure of hippocampal mossy fiber presynaptic terminals and functional hyperexcitability of presynaptic vesicular transmitter release. Mossy fiber terminals as a whole, their transmitter release active zone and readily-releasable vesicle pool, were greatly increased in size, and there was even sprouting of new mossy fiber terminals into regions where they do not normally synapse. Functionally, these presynaptic glutamatergic terminals showed greatly enhanced rate of vesicular release from the rapidly-recycling vesicle pool and accelerated endocytotic recycling of vesicles. We commenced studies to be completed in year 02 to test the ability of four antiepileptic drugs that act via differing mechanisms levetiracetam, lamotrigine, carbamezipine and topiramate, to control presynaptic vesicular release two months after pilocarpine-induced seizures, when the brain has become spontaneously epileptic. We also discovered that the presynaptic vesicle protein dynamin, which is an essential component of one vesicle recycling pathway, is markedly down-regulated in expression and the dynamin pathway loses its ability to keep up with vesicular release in the epileptic brain. If we can find agents that can control presynaptic release, and do so even after development of epilepsy when release is enhanced, we would have a whole new class of treatments to help the 40 of epileptic patients who do not respond to any current therapeutics.

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  • Biology
  • Medicine and Medical Research
  • Pharmacology

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