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Drug Repositioning in Epilepsy Reveals Novel Antiseizure Candidates

Drug Repositioning in Epilepsy Reveals Novel Antiseizure Candidates

Leo Brueggeman, Morgan L Sturgeon, Russell M Martin, Andrew J Grossbach, Yasunori Nagahama, Angela Zhang, Mathew A Howard 3rd, Hiroto Kawasaki, Shu Wu, Robert A Cornell, Jacob J Michaelson, Alexander G Bassuk

Ann Clin Transl Neurol. 2018 Dec 11;6(2):295-309.

PMID: 30847362

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP33401944	Pyrantel tartrate		33401-94-4	Price

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