Published online Jul 19, 2020. doi: 10.5498/wjp.v10.i7.150
Peer-review started: December 31, 2019
First decision: April 3, 2020
Revised: April 25, 2020
Accepted: May 26, 2020
Article in press: May 26, 2020
Published online: July 19, 2020
Epilepsy is a complex neurological disorder characterized by recurrent, unprovoked seizures resulting from the sudden abnormal discharge of brain neurons. It leads to transient brain dysfunction, manifested by abnormal physical movements and consciousness. It can occur at any age, affecting approximately 65 million worldwide, one third of which are still estimated to suffer from refractory seizures. The molecular mechanism of epilepsy is still not fully understood; thus, there is a lack of effective clinical treatment. Therefore, building relevant preclinical models is imperative for screening therapeutics for this disease.
There is an urgent need for further establishment of seizure models in animals, including acute epilepsy models and persistent epilepsy models. These models could be used to study the mechanism of epilepsy and identify novel anti-epileptic therapeutics in the future.
The main objective was to compare three administration modes for establishing a seizure model caused by N-Methyl-D-aspartic acid (NMDA) in zebrafish.
Three administration modes of NMDA, including immersion, intravitreal injection and intraperitoneal injection, were compared with regard to their effects on inducing seizure-like behaviors in adult zebrafish. We evaluated neurotoxicity by observing behavioral changes in zebrafish and graded those behaviors with a seizure score. Statistical analysis was performed based on records to calculate time points and duration of abnormal behavior in zebrafish. All data were analyzed by t-test using GraphPad PRISM 7.00. Analysis of variance was then performed to assess the differences in seizure and latency between experimental groups.
The three NMDA-administration methods triggered different patterns of the epileptic process in adult zebrafish. Seizure scores were increased after increasing NMDA concentration regardless of the mode of administration. However, the curve of immersion continuously rose to a high plateau (after 50 min), while the curves of intravitreal injection and intraperitoneal injection showed a spike in the early stage (10-20 min) followed by a steady decrease in seizure scores. Furthermore, pretreatment with resveratrol and MK-801 significantly delayed seizure onset time and lowered seizure scores.
Intravitreal injection of NMDA was the most suitable route for establishing an acute epileptic model in zebrafish, while immersion with NMDA may be an appropriate method for inducing persistent seizures. Additionally, MK-801 and resveratrol showed strong anti-epileptic effects; thus, both of them may be clinically valuable treatments for epilepsy.
Further study using our models to perform antiepileptic drug screening is necessary, and further work is needed to explore the mechanism of resveratrol against epilepsy.