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

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.