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. There is an urgent need for further establishment of seizure models in animals, which provides an approach to model epilepsy and could be used to identify novel anti-epileptic therapeutics in the future.
To compare three administration modes for establishing a seizure model caused by N-Methyl-D-aspartic acid (NMDA) in zebrafish.
Three administration routes 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. In addition, the protective effects of MK-801 (Dizocilpine) and natural active constituent resveratrol against NMDA-induced alterations were studied.
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.
By comparing the three methods of administration, intravitreal injection of NMDA was the most suitable for establishing an acute epileptic model in zebrafish. Thus, intraperitoneal injection in zebrafish can be applied to simulate diseases such as epilepsy. In addition, NMDA immersion may be an appropriate method to induce persistent seizures. Moreover, MK-801 and resveratrol showed strong anti-epileptic effects; thus, both of them may be clinically valuable treatments for epilepsy.
Core tip: This is the first study to systematically compare the three main administration modes to establish a seizure model in zebrafish. A newly developed zebrafish model with acute and sustained experimental epileptic behavior enables us to study and identify potential mechanisms and screen anti-epileptic drugs. Direct administration of N-Methyl-D-aspartic acid stimulates abnormal excitations of brain nerve cells to simulate epileptic seizures. This study demonstrated that intravitreal injection can be used to establish an acute epilepsy model and immersion can be used as a persistent epilepsy model. The protective effects of resveratrol and MK-801 on the epileptic process were also confirmed, which may have clinical application value.