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

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.

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

“…The PTZ-induced model of tonic-clonic seizures in zebrafish is commonly used for initial screening of potential natural − and synthetic anticonvulsant agents. , Larval zebrafish, when incubated in PTZ solution, experience seizures that behaviorally manifested as a hyperactivity. , Recently, however, it was revealed that relying on the locomotor changes when assessing antiseizure activity of compounds may give false positive results . Therefore, final confirmation should be done using electroencephalographic (EEG) assay.…”

Neurokine fam19a5a/tafa5a regulates anxiety-like behaviors in zebrafish

“…To explore whether these altered activities were provoked by changes in neurotransmitter levels, we measured the levels of various neurotransmitters in wild-type and knockout brains [32]. However, we observed no signi cant changes in neurotransmitters, such as glutamate, GABA, dopamine, serotonin, histamine, and norepinephrine, in either wild-type or knockout brains (Fig.…”

“…To assess neurotransmitter levels in the adult brain, we performed a protocol identical to that previously described [32]. Each fam19a5a-wild-type and fam19a5a-knockout brain (n = 12) was added to nine volumes (w/v) of pre-chilled distilled water and homogenized on ice using a probe sonicator (Ultrasonic processor VCX-130, Sonics & Materials Inc., Newtown, CT, USA).…”

Neurobehavioral Effects of Fermented Rice Bran Extract in Zebrafish Larvae Model

“…The zebrafish (Danio rerio) is a promising vertebrate for the screening of the central nervous system (CNS) with a high degree of genetic compatibility, and it also displays comprehensive neurochemistry similar to human beings [14,15]. The zebrafish's organ formation and pharmacokinetic system are very similar to those of humans [16,17].…”