Drug repositioning in epilepsy reveals novel antiseizure candidates

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.

Phenotypic analysis of catastrophic childhood epilepsy genes: The Epilepsy Zebrafish Project

“…Although simple locomotor readouts have grown popular as seizure assays [69][70][71][72][73][74] , this study emphasizes the rigor necessary to accurately identify epileptic phenotypes in zebrafish and suggests that sole reliance on behavior may lead to misleading conclusions during phenotyping and/or drug discovery efforts.…”

Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis

“…Generally, drug repurposing refers to dig out the new usage of clinically approved drugs and dosage forms for existing drugs or drug candidates. In order to reduce the time period in the process of drug development, it is rational to develop antiepileptic drugs by drug repositioning ( Brueggeman et al, 2019 ). Compared with the development of new drugs, this approach has the advantage of tolerable pharmacokinetic, pharmacodynamic and toxicological properties ( Nosengo, 2016 ).…”

The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial

“…Metformin may have an anti-epileptic effect via a number of different pathways: inhibition of MTOR, activation of AMPK and prevention of oxidative damage induced by seizure activity. Metformin has been shown to suppress seizures in some rodent models and Bruegeman et al have recently demonstrated that metformin significantly suppressed seizure behaviour in a zebrafish PTZ-induced seizure model [33][34][35]. Metformin has not previously been studied in any clinical trial for human seizures or epilepsy.…”