Faculty Collaboration Database

Flavones-bound in benzodiazepine site on GABA_A receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by Isovitexin and 6-C-glycoside-Diosmetin. Eur J Pharmacol 2018 Jul 15;831:77-86

Date

05/09/2018

Pubmed ID

29738701

DOI

10.1016/j.ejphar.2018.05.004

Scopus ID

2-s2.0-85047086011 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

Increasing evidence suggests that flavones can modulate memory and anxiety-like behaviour. However, these therapeutic effects are inconsistent and induce of adverse effects, which have been associated with interactions at the Benzodiazepine (BZ)-binding site. To improve our understanding of flavone effects on memory and anxiety, we employed a plus-maze discriminative avoidance task. Furthermore, we evaluated the potential of the compounds in modulating GABA_A receptors via BZ-binding site using molecular modelling studies. Adult male Wistar rats were treated 30 min before training session with Vicenin-2 (0.1 and 0.25 mg/kg), Vitexin (0.1 and 0.25 mg/kg), Isovitexin (0.1 and 0.25 mg/kg) and 0.1 mg/kg 6-C-glycoside-Diosmetin, vehicle and a GABA_A receptor agonist. The analysis of the time spent in the non-aversive vs aversive enclosed arms during the test session and percentage of time in the open arms within the training session revealed that treatment with Isovitexin and 6-C-glycoside-Diosmetin had memory-enhancing and anxiolytic-like effects (P < 0.001). In contrast, treatment with a higher dose of Diazepam impaired short-and long-term memory when it alleviated anxiety level. Docking studies revealed that flavones docked in a very similar way to that observed to the Diazepam, except by a lack of interaction in residue α1His101 in the BZ-binding site on GABA_A receptors, which may be related to memory-enhancing effect. The occurrence of the α₁His101 interaction could justify the memory-impairing observed following Diazepam treatment. These findings provide the first evidence that Isovitexin and 6-C-glycoside-Diosmetin could exert their memory-enhancing and anxiolytic-like effects via GABA_A receptor modulation, which likely occurs via their benzodiazepine-binding site.

Author List

Oliveira DR, Todo AH, Rêgo GM, Cerutti JM, Cavalheiro AJ, Rando DGG, Cerutti SM

Author

Daniela R. Rodrigues de Oliveira Research Scientist I in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Anti-Anxiety Agents
Apigenin
Avoidance Learning
Behavior, Animal
Binding Sites
Brain
Cognition
Diazepam
Discrimination Learning
Dose-Response Relationship, Drug
Flavonoids
Locomotion
Male
Maze Learning
Memory, Long-Term
Memory, Short-Term
Molecular Docking Simulation
Nootropic Agents
Protein Binding
Protein Conformation
Rats, Wistar
Receptors, GABA-A
Time Factors