GABAA receptor participation in anxiolytic and anticonvulsant effects of (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one in adult zebrafish

Francisco Rogênio Silva Mendes; Antonio Wlisses da Silva; Maria Kueirislene Amâncio Ferreira; Emanuela de Lima Rebouças; Emanuelle Machado Marinho; Márcia Machado Marinho; Paulo Nogueira Bandeira; Alexandre Magno Rodrigues Teixeira; Jane Eire Silva Alencar de Menezes; Erlania Alves de Siqueira; Ramon Róseo Paula Pessoa Bezerra de Menezes; Emmanuel Silva Marinho; Hélcio Silva Dos Santos

doi:10.1016/j.neuint.2022.105303

GABA_A receptor participation in anxiolytic and anticonvulsant effects of (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one in adult zebrafish

Neurochem Int. 2022 May:155:105303. doi: 10.1016/j.neuint.2022.105303. Epub 2022 Feb 17.

Authors

Francisco Rogênio Silva Mendes¹, Antonio Wlisses da Silva², Maria Kueirislene Amâncio Ferreira³, Emanuela de Lima Rebouças¹, Emanuelle Machado Marinho⁴, Márcia Machado Marinho⁵, Paulo Nogueira Bandeira⁶, Alexandre Magno Rodrigues Teixeira¹, Jane Eire Silva Alencar de Menezes³, Erlania Alves de Siqueira⁷, Ramon Róseo Paula Pessoa Bezerra de Menezes⁷, Emmanuel Silva Marinho⁸, Hélcio Silva Dos Santos⁹

Affiliations

¹ Department of Biological Chemistry, Regional University of Cariri, CE, Brazil.
² State University of Ceara, Graduate Program of Biotechnology, Fortaleza, CE, Brazil.
³ State University of Ceara, Graduate Program in Natural Sciences, Fortaleza, CE, Brazil.
⁴ Federal University of Ceara, Department of Analytical and Physical Chemistry, Fortaleza, CE, Brazil.
⁵ State University of Ceara, Iguatu Faculty of Education, Science and Letters, Iguatu, CE, Brazil.
⁶ State University of Vale do Acaraú, Chemistry Course, Sobral, CE, Brazil.
⁷ Federal University of Ceará, Department of Clinical and Toxicological Analysis, Fortaleza, CE, Brazil.
⁸ State University of Ceara, Department of Chemistry, Limoeiro do Norte, CE, Brazil.
⁹ Department of Biological Chemistry, Regional University of Cariri, CE, Brazil; State University of Ceara, Graduate Program of Biotechnology, Fortaleza, CE, Brazil; State University of Ceara, Graduate Program in Natural Sciences, Fortaleza, CE, Brazil; State University of Vale do Acaraú, Chemistry Course, Sobral, CE, Brazil. Electronic address: helcio_santos@uvanet.br.

PMID: 35183661
DOI: 10.1016/j.neuint.2022.105303

Abstract

Anxiety is a mental disorder that affects 25% of patients with epilepsy, and treatments for anxiety and seizures involve the use of benzodiazepines, a class of drugs that have many adverse effects such as decreased motor coordination, drowsiness, and sedation. Thus, new types of drugs with minimal side effects are of immediate requirement. Chalcones comprise a class of compounds with important therapeutic potential and have recently been investigated for their potential as anxiolytic and anticonvulsant agents. Therefore, this study aimed to evaluate the anxiolytic and anticonvulsant effects of the synthetic chalcone (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one (FURCHAL) using adult zebrafish as an animal model. Anxiolytic potential was assessed using the light/dark test and the anticonvulsant effect in 3-stage pentylenetetrazol (PTZ)-induced seizure tests. The mechanisms of the anxiolytic effect were analyzed using γ-aminobutyric acid (GABA) and the serotoninergic system. The anxiolytic effect of FURCHAL was verified by a reduction in fish locomotion, similar to diazepam (DZP), which may involve the GABA_A receptor, as there was no reversal in the anxiolytic behavior of animals treated with FURCHAL by serotonergic antagonists. In addition, pretreatment with flumazenil blocked the anticonvulsant effect of FURCHAL and DZP at all three stages, indicating that FURCHAL also has anticonvulsant effects and that the presence of the α,β unsaturated aromatic system and heterocyclic moiety in FURCHAL provided greater affinity for the GABA_A receptors. Molecular docking revealed that the interactions involved in the formation of the protein-binding complex FURCHAL-GABA_A are formed by three H-bonds involving the oxygen atoms of FURCHAL, and notably, complexes operated in the same region of the DZP site. Thus, this study adds new evidence and highlights that FURCHAL can potentially be used to develop compounds with anxiolytic and anticonvulsant properties.

Keywords: Anxiolytic effect; Benzodiazepines; Convulsion; Zebrafish.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Anxiety Agents* / pharmacology
Anti-Anxiety Agents* / therapeutic use
Anticonvulsants / pharmacology
Anticonvulsants / therapeutic use
Furans
Humans
Molecular Docking Simulation
Receptors, GABA-A
Zebrafish
gamma-Aminobutyric Acid

Substances

Anti-Anxiety Agents
Anticonvulsants
Furans
Receptors, GABA-A
gamma-Aminobutyric Acid
furan