Drug repositioning in epilepsy reveals novel antiseizure candidates


Objective: Epilepsy treatment falls short in ~30% of cases. A better understanding
of epilepsy pathophysiology can guide rational drug development in
this difficult to treat condition. We tested a low-cost, drug-repositioning strategy
to identify candidate epilepsy drugs that are already FDA-approved and
might be immediately tested in epilepsy patients who require new therapies.
Methods: Biopsies of spiking and nonspiking hippocampal brain tissue from
six patients with unilateral mesial temporal lobe epilepsy were analyzed by
RNA-Seq. These profiles were correlated with transcriptomes from cell lines
treated with FDA-approved drugs, identifying compounds which were tested
for therapeutic efficacy in a zebrafish seizure assay. Results: In spiking versus
nonspiking biopsies, RNA-Seq identified 689 differentially expressed genes, 148
of which were previously cited in articles mentioning seizures or epilepsy. Differentially
expressed genes were highly enriched for protein–protein interactions
and formed three clusters with associated GO-terms including myelination,
protein ubiquitination, and neuronal migration. Among the 184 compounds, a
zebrafish seizure model tested the therapeutic efficacy of doxycycline, metformin,
nifedipine, and pyrantel tartrate, with metformin, nifedipine, and
pyrantel tartrate all showing efficacy. Interpretation: This proof-of-principle
analysis suggests our powerful, rapid, cost-effective approach can likely be
applied to other hard-to-treat diseases.