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Review
. 2023 Aug 31:14:1213969.
doi: 10.3389/fneur.2023.1213969. eCollection 2023.

Toward the use of novel alternative methods in epilepsy modeling and drug discovery

Claudia Miguel Sanz  1 , Miriam Martinez Navarro  1 , Daniel Caballero Diaz  1 , Gentzane Sanchez-Elexpuru  1 , Vincenzo Di Donato  1
Affiliations
Review

Toward the use of novel alternative methods in epilepsy modeling and drug discovery

Claudia Miguel Sanz et al. Front Neurol. .

Abstract

Epilepsy is a chronic brain disease and, considering the amount of people affected of all ages worldwide, one of the most common neurological disorders. Over 20 novel antiseizure medications (ASMs) have been released since 1993, yet despite substantial advancements in our understanding of the molecular mechanisms behind epileptogenesis, over one-third of patients continue to be resistant to available therapies. This is partially explained by the fact that the majority of existing medicines only address seizure suppression rather than underlying processes. Understanding the origin of this neurological illness requires conducting human neurological and genetic studies. However, the limitation of sample sizes, ethical concerns, and the requirement for appropriate controls (many patients have already had anti-epileptic medication exposure) in human clinical trials underscore the requirement for supplemental models. So far, mammalian models of epilepsy have helped to shed light on the underlying causes of the condition, but the high costs related to breeding of the animals, low throughput, and regulatory restrictions on their research limit their usefulness in drug screening. Here, we present an overview of the state of art in epilepsy modeling describing gold standard animal models used up to date and review the possible alternatives for this research field. Our focus will be mainly on ex vivo, in vitro, and in vivo larval zebrafish models contributing to the 3R in epilepsy modeling and drug screening. We provide a description of pharmacological and genetic methods currently available but also on the possibilities offered by the continued development in gene editing methodologies, especially CRISPR/Cas9-based, for high-throughput disease modeling and anti-epileptic drugs testing.

Keywords: 3Rs; Dravet syndrome; alternative methods; anti-epileptic drug screening; epilepsy; genetic models; zebrafish.

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Conflict of interest statement

All authors are employees of ZeClinics SL, a contract research organization using the zebrafish model for research in disease modeling, target validation and drug screening.

Figures

Figure 1
Figure 1
Timeline of the most representative vertebrate animal models in epilepsy over the last century. All models (exception of the electroshock models in cats) are still being used in the development of new treatments for epilepsy. During the first half of the twentieth century and up to the late 1990s, a large number of compounds with antiepileptic properties were discovered in these models (Classics ASMs). However, most of these compounds were discovered in pharmacoresistant models of epilepsy. The development of the first genetic models has allowed progress to be scored in the search for novel antiseizure medications that are able to overcome drug resistance. In the last decade, the use of zebrafish has led to the development of Fenfluramine (FDA-approved drug) and Clemizole (in DS clinical phases). In the future, it is hoped that new approach methodologies (NAMs), such as zebrafish, organoids and induced Pluripotent Stem Cells (iPSCs), will facilitate the discovery of new drugs useful for different types of epilepsy (new ASMs).
Figure 2
Figure 2
Comparison chart of the alternative methods available for epilepsy research. Comparison table describing the characteristics of the alternative methods discussed in this review, including OSCs, iPSCs, brain organoids and zebrafish models. MoA, Mechanism of Action.
See this image and copyright information in PMC

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