In the United States alone, over 3 million people have been diagnosed with epilepsy, a dynamic disease characterized by recurring and unpredictable seizures. Antiepileptic drugs (AEDs) and other therapies have helped to combat this widespread phenomenon, yet for one-third of epilepsy patients, there is still no effective treatment. A better understanding of the mechanisms of AEDs has been called for. Levetiracetam (LEV) is one AED on the market that does not work by the typical mechanisms of action of AEDs. LEV binds to the vesicular protein SV2A in neurons in the brain, which is thought to mediate some step in neurotransmitter release. However, the exact mechanism of action of LEV is unknown. Deducing this mechanism would be of substantial benefit for the development of new, similar drugs that also work by such a non-conventional mechanism. The experiments and results I present in this dissertation detail my investigation of the effect of LEV on neurotransmission of rat hippocampal neurons. My methods include fluorescence-staining with FM dyes to label synaptic vesicles and monitor vesicle release as well as electrophysiological techniques to observe synaptic currents. My experimental protocols have allowed me to detect differences in neurotransmitter release in LEV-treated neurons. Furthermore, manipulating exposure conditions required before LEV action have allowed me to deduce that LEV must enter active neurons to reach SV2A. I believe that LEV is dependent on endocytosis for access to vesicles, a completely unique mechanism of action for a small molecule drug.
University of Minnesota Ph.D. dissertation. July 2011. Major: Neuroscience. 1 computer file (PDF); iv, 66 pages.
Meehan, Anna L..
Identifying the mechanism of action of the antiepileptic drug levetiracetam in synaptic vesicle release and its implications for epilepsy..
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