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. doi: 10.1016/j.ejphar.2018.05.004. Epub 2018 May 5.

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 GABAA 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 GABAA 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 GABAA 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 GABAA receptor modulation, which likely occurs via their benzodiazepine-binding site.

Keywords: Anxiety and memory; Flavones; GABAAR; PM-DAT.

Publication types

  • Comparative Study

MeSH terms

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

Substances

  • 6-C-glycoside-diosmetin
  • Anti-Anxiety Agents
  • Flavonoids
  • Nootropic Agents
  • Receptors, GABA-A
  • Apigenin
  • isovitexin
  • Diazepam