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Title: Flavones-bound in benzodiazepine site on GABA(A) receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by Isovitexin and 6-C-glycoside-Diosmetin
Authors: Oliveira, Daniela Rodrigues de [UNIFESP]
Todo, Andreia Hatsue [UNIFESP]
Rego, Gizelda Maia
Cerutti, Janete Maria [UNIFESP]
Cavalheiro, Alberto Jose
Rando, Daniela Goncales Galasse [UNIFESP]
Cerutti, Suzete Maria [UNIFESP]
Keywords: Flavones
Anxiety and memory
Issue Date: 2018
Publisher: Elsevier Science Bv
Citation: European Journal Of Pharmacology. Amsterdam, v. 831, p. 77-86, 2018.
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 alpha 1His101 in the BZ-binding site on GABAA receptors, which may be related to memory-enhancing effect. The occurrence of the alpha 1His101 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.
ISSN: 0014-2999
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