Abstracts

Rationale: To identify new drugs to treat epileptic individuals, our lab developed a medium throughput screening method, using Drosophila Melanogaster, to repurpose previously FDA or otherwise approved chemical libraries for their ability to suppress seizures.

Methods: We previously established a fly model that successfully recapitulates the seizure phenotype observed in Duplication 15q syndrome (Dup15q) individuals by overexpressing Drosophila Ube3a (Dube3a) in glial cells. Here we evaluate 70 compounds from the Screen-Well Ion Channel Ligand Library for their ability to suppress seizures in our glial cell specific epilepsy model. The primary screen was composed of 24 calcium channel modulators, 23 potassium channel modulators, 10 sodium channel modulators, 7 intracellular calcium modulators, and 6 other miscellaneous drugs. repo >Dube3a were raised on food containing 1 of the 70 compounds and subjected to a Bang Sensitivity Assay (BSA). If at least 50% of repo >Dube3a flies were in the non-seizure group, the drug passed primary screening. For secondary confirmation screening, flies were either raised on control food or drug food. If recovery time for repo >Dube3a flies was at least 50% faster on drug food, for both males and females, the drug passed secondary screening.

Results: We identified 8 compounds that suppress seizures in repo >Dube3a flies by at least 50%. Seventy-five percent of these compounds are potassium modulators and 25% are calcium modulators. ATP-sensitive Inward Rectifying K+ channel (KATP) modulation is a shared commonality among 3 of the 8 compounds. To evaluate the potentially critical role KATP modulation plays in seizure suppression, as well as to investigate the importance of glial-specific neuronal modulation, we are currently testing drug efficacy on flies that simultaneously express Dube3a and an RNAi against the Drosophila homologue for KATP (Irk) in glial cells.

Conclusions: We expect to find that KATP modulators fail to suppress seizures in the absence of sufficient irk channel expressions. These studies will lead directly to new candidate drugs, specific ion channel agonists and antagonists, that may eventually be used clinically to suppress seizures in Dup15q syndrome.

Funding: Please list any funding that was received in support of this abstract.: This research was funded by NIH NINDS grants 1R01NS115776-01A1 & 5R21HD091541-02 awarded to Lawrence T. Reiter.