Background

Epilepsy is a common neurological disorder, marked by abnormal synchronous brain activity (seizures), typically characterized by a sudden brief period of altered or lost consciousness, involuntary movements or convulsions. Epilepsy affects about 50 million people worldwide and 30% of patients are currently resistant to available medication.

Millions of epilepsy patients continue to experience debilitating seizures despite a considerable number of registered antiepileptic drugs (AEDs). These AEDs have a narrow spectrum of mechanisms of action (MOA). Most of them typically act by reinforcing GABAergic inhibition or by blocking voltage-gated sodium channels, effective mechanisms but with unwanted side effects. Thus, the search for new drugs with novel MOAs, improved activity and fewer adverse effects remains highly relevant.

There is a need for innovative therapies that are not merely symptomatic (i.e. that suppress seizures), but that can actually prevent epilepsy (anti-epileptogenic) or halt its progression (disease modification). There is growing recognition in the field that novel insights into the etiology and treatment of this debilitating condition will be gained through neurodevelopmental models – animal models with alterations in neurological development, leading to the subsequent emergence of clinically relevant phenotypes.

The need is also urgent for the rapid functional evaluation of candidate genes (identified by next generation sequencing, GWAS, EWAS, and CNV analysis) and potential drug targets (identified by omics and systems biology analysis), prior to their in vivo characterization and validation in mice. Similarly, there is a clear need for novel rapid in vivo screening tools to identify bioactive drug-like small molecules. Zebrafish are now established as an attractive in vivo system for the high-throughput analysis of behavior and as a novel experimental model for epilepsy. In zebrafish larvae, the GABAA antagonist PTZ induces clonus-type convulsions characteristic of epilepsy in mammals.

Electrophysiological recordings from PTZ-treated zebrafish larvae indicated epileptiform discharges that were reduced by AEDs such as valproate and diazepam. Using an automated video tracking system to monitor larval movement in microtiter plates, AEDs were found to similarly suppress PTZ-induced seizure-like behaviors and electrographic activity in zebrafish and mice, validating the suitability of zebrafish for AED discovery (Afrikanova et al., 2013). Several 'hit' compounds identified in zebrafish, also exhibited clear anticonvulsant activity in rodent seizure models tested (mouse PTZ, rat limbic seizure, 6 Hz).

In her previous role as senior scientist at the University of Leuven, Belgium, Dr. Esguerra and collaborators (in both industry and academia) generated a pharmacoresistant seizure model in both mice and zebrafish using the proconvulsant allylglycine. The work in Leuven also led to the establishment of two zebrafish models for Dravet syndrome, a severe early-onset epilepsy, using antisense knockdown (KD) – one of SCN1a, and the other of a novel candidate gene in epileptic encephalopathies (EE), CHD2. SCN1a KD larvae display spontaneous seizures, are hyperthermia (fever)-sensitive, and respond to AEDs similar to human patients. Further work on CHD2 revealed it to be a risk factor for photosensitive EE while another study proved the role of the presynaptic protein STX1B, in fever-associated epilepsy syndromes.

Published June 8, 2015 1:45 PM - Last modified Dec. 17, 2015 8:31 AM