PHARMACOLOGY
Pharmacological and Genetic Rescue of Idiopathic Epilepsies
Lyndsey Leigh Anderson
Dissertation under the direction of Professor Alfred George, Jr.
Epilepsy is a common neurological disorder affecting approximately 1% of the population worldwide. Many epilepsy patients achieve complete seizure control with current antiepileptic drugs; however, these medications fail to control seizures in 30% of patients, highlighting the need for novel treatments and for research into the underlying molecular mechanisms of epilepsy. Mutations within voltage-gated sodium channels have been identified in association with epilepsy and several mouse models have been generated to understand how these disease-associated mutations manifest in epilepsy development. The genetically engineered mouse line, Scn2aQ54, expresses a transgene encoding an inactivation-impaired neuronal Nav1.2 channel. Mice expressing the Scn2aQ54 transgene exhibit a severe epilepsy phenotype correlated with increased persistent sodium current in hippocampal neurons. We investigated the antiepileptic potential of preferential persistent sodium current inhibition using ranolazine and the novel compound, GS967. We observed that both ranolazine and GS967 reduced seizure frequency in Scn2aQ54 mice, and GS967 inhibited spontaneous action potential firing in neurons isolated from Scn2aQ54 mice. GS967 was also effective at protecting against seizures in the maximal electroshock model. Additionally, we found that long-term treatment with GS967 improved survival, prevented neuron loss and suppressed mossy fiber sprouting in Scn2aQ54 mice. Heterozygous Scn1a knockout (Scn1a+/-) mice recapitulate the phenotype of Dravet syndrome such as spontaneous seizures and premature lethality. Electrophysiological studies in dissociated hippocampal neurons from Scn1a+/- mice have shown a reduced sodium current density and impaired excitability in GABAergic interneurons suggesting that impaired GABA-mediated inhibition underlies the pathophysiology of Dravet syndrome. We generated a mouse line in which SCN1A is selectively expressed in GABAergic interneurons to directly test the hypothesis that the epilepsy phenotype in Scn1a+/- mice can be rescued by restoring SCN1A in GABAergic interneurons. Utilizing this genetic approach, we were not able to attenuate the reduced lifespan of Scn1a+/- mice by restoring SCN1A selectively in interneurons, suggesting that additional mechanisms may contribute to the reduced survival of Dravet syndrome. However, pharmacological intervention with GS967 was able to successfully rescue the lifespan of Scn1a+/- mice. These results suggest that GS967 is an effective novel antiepileptic drug that can be utilized to probe the pathophysiology of epilepsy.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03182014-152959 |
| Date | 18 March 2014 |
| Creators | Anderson, Lyndsey Leigh |
| Contributors | Gregg Stanwood, Alfred George, Vsevolod Gurevich, Robert Macdonald, Jennifer Kearney |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03182014-152959/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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