<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Aim/objective.</bold> When applied in pharmacological doses, the indole derivative melatonin exhibits neuroactive and neuroprotective effects. Indoles and their metabolites, such as kynurenine, are ligands of aryl hydrocarbon receptors (AhR). This study aimed to evaluate the antiepileptic and analgesic activity of melatonin and two synthetic melatonin derivatives. The possible involvement of AhR and kynurenine in their neuropharmacological effects were also tested.<bold>Methods.</bold> The tested substances were: melatonin, two melatonin derivatives bearing aryl hydrocarbon moiety with either furyl or thienyl substitute (3e and 3f), and alpha naphthoflavone (ANF), an antagonist of AhR. After intraperitoneal injection of 30, 100, or 300 mg/kg of the tested agents for seven days, male mice ICR (25-30 g) were subjected to a corneal kindling seizure model. Two tests for analgesia, i.e., the hot plate test and the formalin test, were also applied. AhR and kynurenine concentrations were evaluated in brain homogenates.<bold>Results.</bold> Substances 3e and 3f demonstrated an antiepileptic activity comparable to that of melatonin. Some analgesic activity was also shown, albeit lower than that of melatonin in equivalent doses. For melatonin and 3f treated mice, dose-dependent increases in AhR and kynurenine levels in brain homogenates were recorded. The antagonist ANF neither blocks the antiseizure activity of the tested indoles, nor demonstrated analgesic activity.<bold>Conclusion.</bold> Melatonin and the two tested melatonin-aroylhydrazone derivatives bearing either furyl or thienyl substitute exhibit antiepileptic and analgesic activity. Our results did not support the involvement of AhR in the demonstrated neurobiological activity. Further studies are needed to elucidate their exact molecular mechanisms.</abstract>

Aim/objective. When applied in pharmacological doses, the indole derivative melatonin exhibits neuroactive and neuroprotective effects. Indoles and their metabolites, such as kynurenine, are ligands of aryl hydrocarbon receptors (AhR). This study aimed to evaluate the antiepileptic and analgesic activity of melatonin and two synthetic melatonin derivatives. The possible involvement of AhR and kynurenine in their neuropharmacological effects were also tested.Methods. The tested substances were: melatonin, two melatonin derivatives bearing aryl hydrocarbon moiety with either furyl or thienyl substitute (3e and 3f), and alpha naphthoflavone (ANF), an antagonist of AhR. After intraperitoneal injection of 30, 100, or 300 mg/kg of the tested agents for seven days, male mice ICR (25-30 g) were subjected to a corneal kindling seizure model. Two tests for analgesia, i.e., the hot plate test and the formalin test, were also applied. AhR and kynurenine concentrations were evaluated in brain homogenates.Results. Substances 3e and 3f demonstrated an antiepileptic activity comparable to that of melatonin. Some analgesic activity was also shown, albeit lower than that of melatonin in equivalent doses. For melatonin and 3f treated mice, dose-dependent increases in AhR and kynurenine levels in brain homogenates were recorded. The antagonist ANF neither blocks the antiseizure activity of the tested indoles, nor demonstrated analgesic activity.Conclusion. Melatonin and the two tested melatonin-aroylhydrazone derivatives bearing either furyl or thienyl substitute exhibit antiepileptic and analgesic activity. Our results did not support the involvement of AhR in the demonstrated neurobiological activity. Further studies are needed to elucidate their exact molecular mechanisms.

Aryl Hydrocarbon Receptors in Indole Derivative Treated Mice: Neuropharmacological Perspectives

Department of Pharmacology and Toxicology, Faculty of Medicine

Department of Chemistry, Faculty of Pharmacy

Department of Pathophysiology, Faculty of Medicine

Acta Medica Bulgarica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Aim/objective. When applied in pharmacological doses, the indole derivative melatonin exhibits neuroactive and neuroprotective effects. Indoles and their...

Aryl Hydrocarbon Receptors in Indole Derivative Treated Mice: Neuropharmacological Perspectives

Published Online: May 05, 2021

Page range: 25 - 33

Accepted: Jul 26, 2020

DOI: https://doi.org/10.2478/amb-2021-0004

Keywords
melatonin, indole derivatives, corneal kindling, analgesia, aryl hydrocarbon receptors, kynurenine

© 2021 P. Andreeva-Gateva et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Aryl Hydrocarbon Receptors in Indole Derivative Treated Mice: Neuropharmacological Perspectives

Published Online: May 05, 2021

Page range: 25 - 33

Accepted: Jul 26, 2020

DOI: https://doi.org/10.2478/amb-2021-0004

Keywordsmelatonin, indole derivatives, corneal kindling, analgesia, aryl hydrocarbon receptors, kynurenine

© 2021 P. Andreeva-Gateva et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
melatonin, indole derivatives, corneal kindling, analgesia, aryl hydrocarbon receptors, kynurenine