Efficacy and pharmacokinetics evaluation of 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1, 2, 4-oxadiazol-5(4H)-one (GM-90432) as an anti-seizure agent. (December 2020)

• Record Type: Journal Article
• Authors: Hwang, Kyu-Seok; Kan, Hyemin; Kim, Seong Soon; Chae, Jin Sil; Yang, Jung Yoon; Shin, Dae-Seop; Ahn, Se Hwan; Ahn, Jin Hee; Cho, Jin-Hwa; Jang, Il-Sung; Shin, Junnyeong; Joo, Jaeyoung; Kim, Cheol-Hee; Bae, Myung Ae
• Is Part Of: Neurochemistry international. Volume 141(2020)
• Publication Date: 2020-12
• Subjects: Zebrafish -- Anti-seizure drug -- Electroencephalogram -- Electrophysiology -- Pharmacokinetics; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2020.104870
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Epilepsy is a common chronic neurological disease characterized by recurrent epileptic seizures. A seizure is an uncontrolled electrical activity in the brain that can cause different levels of behavior, emotion, and consciousness. One-third of patients fail to receive sufficient seizure control, even though more than fifty FDA-approved anti-seizure drugs (ASDs) are available. In this study, we attempted small molecule screening to identify potential therapeutic agents for the treatment of seizures using seizure-induced animal models. Through behavioral phenotype-based screening, 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1, 2, 4-oxadiazol-5(4H)-one (GM-90432) was identified as a prototype. GM-90432 treatment effectively decreased seizure-like behaviors in zebrafish and mice with chemically induced seizures. These results were consistent with decreased neuronal activity through immunohistochemistry for pERK in zebrafish larvae. Additionally, electroencephalogram (EEG) analysis revealed that GM-90432 decreases seizure-specific EEG events in adult zebrafish. Moreover, we revealed the preferential binding of GM-90432 to voltage-gated Na + channels using a whole-cell patch clamp technique. Through pharmacokinetic analysis, GM-90432 effectively penetrated the blood-brain barrier and was distributed into the brain. Taken together, we suggest that GM-90432 has the potential to be developed into a new ASD candidate. Highlights: 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1, 2, 4-oxadiazol-5(4H)-one (GM-90432) was identified as an anti-seizure agent. GM-90432 effectively decreased seizure-like behaviors in zebrafish and mouse. Electroencephalogram analysis revealed that GM-90432 mitigate seizure-specific events in adult zebrafish. Electrophysiology analysis implied preferential binding of GM-90432 to voltage-gated Na + channel. Pharmacokinetic analysis suggested that GM-90432 has the potential to be developed into a new ASD candidate.