Neurochemical Effects of 4-(2Chloro-4-Fluorobenzyl)-3-(2-Thienyl)-1,2,4-Oxadiazol-5(4H)-One in the Pentylenetetrazole (PTZ)-Induced Epileptic Seizure Zebrafish Model.

Seong Soon Kim,Byung Hoi Lee,Myung Ae Bae,Jung Yoon Yang,Sung-Hee Cho,Se Hwan Ahn,Yuji Son,Dae-Seop Shin,Hyemin Kan,Kyu-Seok Hwang,Jin Hee Ahn

doi:10.3390/ijms22031285

Abstract

Epilepsy is one of the most common neurological disorders, and it is characterized by spontaneous seizures. In a previous study, we identified 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as a novel anti-epileptic agent in chemically- or genetically-induced epileptic zebrafish and mouse models. In this study, we investigated the anti-epileptic effects of GM-90432 through neurochemical profiling-based approach to understand the neuroprotective mechanism in a pentylenetetrazole (PTZ)-induced epileptic seizure zebrafish model. GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-β-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents.

Highlights

Epilepsy is one of the most common neurological disorders, affecting approximately 65 million people
Numerous studies reported that pentylenetetrazole (PTZ) acts as an antagonist for gamma-aminobutyric acid type A (GABAA) receptor with epileptogenic potential, the toxicological mechanism underlying epileptic seizures has been known to block the binding of gamma-aminobutyric acid (GABA) on the GABAA receptors through in vivo practices [7,8]
To confirm the protective effect of GM-90432 against neurotoxicity induced by PTZ and the possibility of GM-90432 as an anti-seizure agent, we investigated metabolic alteration of neurotransmitters and neurosteroids induced by GM-90432, PTZ, or PTZ after treatment with GM-90432 in the brains of zebrafish

Summary

Introduction

Epilepsy is one of the most common neurological disorders, affecting approximately 65 million people. Previous studies have determined that the molecular mechanisms behind epileptic seizures are associated with imbalanced neurotransmission and abnormal neural activity [3,4]. GABAergic transmission is known as a key modulator of excitatory and inhibitory synaptic potentials in the nervous system. As the primary molecular mechanism underlying epileptic seizure is the inhibition of GABAergic signaling via gamma-aminobutyric acid type A (GABAA) receptors in vivo [7,8], the balance between excitatory and inhibitory signaling (E/I ratio) is especially important. Numerous studies reported that pentylenetetrazole (PTZ) acts as an antagonist for GABAA receptor with epileptogenic potential, the toxicological mechanism underlying epileptic seizures has been known to block the binding of GABA on the GABAA receptors through in vivo practices [7,8]

Methods

Results

Conclusion