Melatonin Pretreatment Protects Against Status epilepticus, Glutamate Transport, and Oxidative Stress Induced by Kainic Acid in Zebrafish.

Ana Caroline Salvador De Farias,Samira Leila Baldin,Eduardo Ronconi Dondossola,Eduardo Pacheco Rico,Henrique Teza Bernardo,Karolyne De Pieri Pickler

doi:10.1007/s12035-021-02579-4

Abstract

Status epilepticus (SE) develops from abnormal electrical discharges, resulting in neuronal damage. Current treatments include antiepileptic drugs. However, the most common drugs used to treat seizures may sometimes be ineffective and have many side effects. Melatonin is an endogenous physiological hormone that is considered an alternative treatment for neurological disorders because of its free radical scavenging property. Thus, this study aimed to determine the effects of melatonin pretreatment on SE by inducing glutamatergic hyperstimulation in zebrafish. Seizures were induced in zebrafish using kainic acid (KA), a glutamate analog, and the seizure intensity was recorded for 60min. Melatonin treatment for 7days showed a decrease in seizure intensity (28%), latency to reach score 5 (14min), and duration of SE (29%). In addition, melatonin treatment attenuated glutamate transporter levels, which significantly decreased in the zebrafish brain after 12h of KA-induced seizures. Melatonin treatment reduced the increase in oxidative stress by reactive oxygen species formation through thiobarbituric acid reactive substances and 2',7'-dichiorofluorescin, induced by KA-seizure. An imbalance of antioxidant enzyme activities such as superoxide dismutase and catalase was influenced by melatonin and KA-induced seizures. Our study indicates that melatonin promotes a neuroprotective response against the epileptic profile in zebrafish. These effects could be related to the modulation of glutamatergic neurotransmission, recovery of glutamate uptake, and oxidative stress parameters in the zebrafish brain.

Highlights

Epilepsy is the second most common neurological disorder with the highest incidence worldwide, characterized by recurrent seizures and abnormal EEG recordings in the brain [1, 2]
No alterations were observed in Glutathione reductase (GR) and Glutathione peroxidases (GPx) activity in any of the groups tested (Fig. 6D-E). This is the first study to investigate the neuroprotective effects of the pretreatment with melatonin against Status epilepticus (SE) induced by kainic acid (KA) in zebrafish
Our findings show that control KA fish spent an average of 41 min in SE, with extremely intense seizures, and a short latency time

Summary

Introduction

Epilepsy is the second most common neurological disorder with the highest incidence worldwide, characterized by recurrent seizures and abnormal EEG recordings in the brain [1, 2]. Seizures emerge from abnormal hyperexcitability and hypersynchronization of neurons, resulting in unprovoked excessive electrical discharges causing glutamatergic excitotoxicity, oxidative stress, and neuronal apoptosis [5]. Among multiple therapeutics targeted for the treatment of epilepsy, the use of antiepileptic drugs (AEDs) is the most common. These medications act on sodium ionic channels, GABAergic, and glutamatergic systems. Current treatment involves the use of multiple drugs to attenuate seizures. The need to find alternative treatments and drugs is growing as treatmentresistant cases are increasing

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