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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

Title
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
Authors
Hwang, Kyu-SeokKan, HyeminKim, Seong SoonChae, Jin SilYang, Jung YoonShin, Dae-SeopAhn, Se HwanAhn, Jin HeeCho, Jin-HwaJang, Il-SungShin, JunnyeongJoo, JaeyoungKim, Cheol-HeeBae, Myung Ae
DGIST 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
Issue Date
2020-12
Citation
Neurochemistry International, 141
Type
Article
Article Type
Article
Author Keywords
ZebrafishAnti-seizure drugElectroencephalogramElectrophysiologyPharmacokinetics
Keywords
BLOOD-BRAIN-BARRIERSODIUM-CHANNELSZEBRAFISHEPILEPSYCARBAMAZEPINELACOSAMIDEPHENYTOINBEHAVIORMODELSDRUGS
ISSN
0197-0186
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.
URI
http://hdl.handle.net/20.500.11750/12827
DOI
10.1016/j.neuint.2020.104870
Publisher
Elsevier BV
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