Journal article
Drug repositioning in epilepsy reveals novel antiseizure candidates
Annals of clinical and translational neurology, Vol.6(2), pp.295-309
02/2019
DOI: 10.1002/acn3.703
PMCID: PMC6389756
PMID: 30847362
Abstract
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.
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.
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.
This proof-of-principle analysis suggests our powerful, rapid, cost-effective approach can likely be applied to other hard-to-treat diseases.
Details
- Title: Subtitle
- Drug repositioning in epilepsy reveals novel antiseizure candidates
- Creators
- Leo Brueggeman - Department of Psychiatry Carver College of Medicine University of Iowa Iowa City IowaMorgan L Sturgeon - The Interdisciplinary Graduate Program in Molecular Medicine Carver College of Medicine University of Iowa Iowa City IowaRussell M Martin - College of Engineering University of Iowa Iowa City IowaAndrew J Grossbach - Department of Neurosurgery University of Iowa Iowa City IowaYasunori Nagahama - Department of Neurosurgery University of Iowa Iowa City IowaAngela Zhang - Department of Biostatistics University of Washington Seattle WashingtonMatthew A Howard III - Department of Neurosurgery University of Iowa Iowa City IowaHiroto Kawasaki - Department of Neurosurgery University of Iowa Iowa City IowaShu Wu - Department of Pediatrics University of Iowa Iowa City IowaRobert A Cornell - Department of Anatomy and Cell Biology University of Iowa Iowa City IowaJacob J Michaelson - Department of Psychiatry Carver College of Medicine University of Iowa Iowa City IowaAlexander G Bassuk - Department of Pediatrics University of Iowa Iowa City Iowa
- Resource Type
- Journal article
- Publication Details
- Annals of clinical and translational neurology, Vol.6(2), pp.295-309
- DOI
- 10.1002/acn3.703
- PMID
- 30847362
- PMCID
- PMC6389756
- NLM abbreviation
- Ann Clin Transl Neurol
- ISSN
- 2328-9503
- eISSN
- 2328-9503
- Publisher
- United States
- Grant note
- R01 NS098590 / NINDS NIH HHS T32 GM007337 / NIGMS NIH HHS
- Language
- English
- Date published
- 02/2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Communication Sciences and Disorders; Psychiatry; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics); Dental Research; Neurosurgery; Otolaryngology; Internal Medicine
- Record Identifier
- 9984020757702771
Metrics
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