1. Academic Validation
  2. Anticonvulsant activity of melatonin and its success in ameliorating epileptic comorbidity-like symptoms in zebrafish

Anticonvulsant activity of melatonin and its success in ameliorating epileptic comorbidity-like symptoms in zebrafish

  • Eur J Pharmacol. 2021 Dec 5;912:174589. doi: 10.1016/j.ejphar.2021.174589.
Qingyu Ren 1 Daili Gao 1 Lei Mou 1 Shanshan Zhang 1 Mengqi Zhang 1 Ning Li 1 Attila Sik 2 Meng Jin 3 Kechun Liu 4
Affiliations

Affiliations

  • 1 Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Ji'nan, 250103, Shandong Province, PR China; Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, 28789 East Jingshi Road, Ji'nan, 250103, Shandong Province, PR China.
  • 2 Institute of Physiology, Medical School, University of Pecs, Pecs, H-7624, Hungary; Szentagothai Research Centre, University of Pecs, Pecs, H-7624, Hungary; Institute of Clinical Sciences, Medical School, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
  • 3 Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Ji'nan, 250103, Shandong Province, PR China; Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, 28789 East Jingshi Road, Ji'nan, 250103, Shandong Province, PR China. Electronic address: [email protected]
  • 4 Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 East Jingshi Road, Ji'nan, 250103, Shandong Province, PR China; Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, 28789 East Jingshi Road, Ji'nan, 250103, Shandong Province, PR China. Electronic address: [email protected]
Abstract

Epilepsy is one of common neurological disorders, greatly distresses the well-being of the sufferers. Melatonin has been used in clinical anti-epileptic studies, but its effect on epileptic comorbidities is unknown, and the underlying mechanism needs further investigation. Herein, by generating PTZ-induced zebrafish seizure model, we carried out interdisciplinary research using neurobehavioral assays, bioelectrical detection, Molecular Biology, and network pharmacology to investigate the activity of melatonin as well as its pharmacological mechanisms. We found melatonin suppressed seizure-like behavior by using zebrafish regular locomotor assays. Zebrafish freezing and bursting activity assays revealed the ameliorative effect of melatonin on comorbidity-like symptoms. The preliminary screening results of neurobehavioral assays were further verified by the expression of key genes involved in neuronal activity, neurodevelopment, depression and anxiety, as well as electrical signal recording from the midbrain of zebrafish. Subsequently, network pharmacology was introduced to identify potential targets of melatonin and its pathways. Real-time qPCR and protein-protein interaction (PPI) were conducted to confirm the underlying mechanisms associated with glutathione metabolism. We also found that melatonin receptors were involved in this process, which were regulated in response to melatonin exposure before PTZ treatment. The antagonists of melatonin receptors affected anticonvulsant activity of melatonin. Overall, current study revealed the considerable ameliorative effects of melatonin on seizure and epileptic comorbidity-like symptoms and unveiled the underlying mechanism. This study provides an animal model for the clinical application of melatonin in the treatment of epilepsy and its comorbidities.

Keywords

Anxiety; Depression; Glutathione metabolism; Network pharmacology.

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