Flavones-bound in benzodiazepine site on GABA(A) receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by Isovitexin and 6-C-glycoside-Diosmetin

Flavones-bound in benzodiazepine site on GABA(A) receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by Isovitexin and 6-C-glycoside-Diosmetin

Author Oliveira, Daniela Rodrigues de Autor UNIFESP Google Scholar
Todo, Andreia Hatsue Autor UNIFESP Google Scholar
Rego, Gizelda Maia Google Scholar
Cerutti, Janete Maria Autor UNIFESP Google Scholar
Cavalheiro, Alberto Jose Google Scholar
Rando, Daniela Goncales Galasse Autor UNIFESP Google Scholar
Cerutti, Suzete Maria Autor UNIFESP Google Scholar
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.
Keywords Flavones
GABAAR
Anxiety and memory
PM-DAT
Language English
Sponsor Sao Paulo State Research Foundation (FAPESP)
Brazilian Agricultural Research Corporation (EMBRAPA)
Nuclei of Bioassay, Biosynthesis and Ecophysiology of Natural Products (NuBBE)
Grant number FAPESP: 2009/15229-8
FAPESP: 2013/01875-0
Date 2018
Published in European Journal Of Pharmacology. Amsterdam, v. 831, p. 77-86, 2018.
ISSN 0014-2999 (Sherpa/Romeo, impact factor)
Publisher Elsevier Science Bv
Extent 77-86
Origin http://dx.doi.org/10.1016/j.ejphar.2018.05.004
Access rights Closed access
Type Article
Web of Science ID WOS:000433249600010
URI http://repositorio.unifesp.br/handle/11600/45959

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