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

Autor(es)

de Oliveira, Daniela Rodrigues ^{[1, 2, 3]} ; Todo, Andreia Hatsue ^[4] ; Rego, Gizelda Maia ^[5] ; Cerutti, Janete Maria ^[1] ; Cavalheiro, Alberto Jose ^[6] ; Galasse Rando, Daniela Goncales ^[4] ; Cerutti, Suzete Maria ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Morfol & Genet, Lab Bases Genet Tumor Tiroide, Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Ciencias Biol, Lab Farmacol Celular & Comportamental, Diadema, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Patol, Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Med Chem Res Grp, Diadema, SP - Brazil

^[5] Brazilian Agr Res Corp EMBRAPA, Dept Forestry Colombo, Colombo, Parana - Brazil

^[6] Sao Paulo State Univ, Nuclei Bioassay Biosynth & Ecophysiol Nat Prod Nu, UNESP, Araraquara, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 831, p. 77-86, JUL 15 2018.
• Citações Web of Science: 3

Resumo

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. (AU)

• Processo FAPESP: 09/15229-8 - Análise da expressão de receptores glutamatérgico, serotoninérgico e GABAérgico na amígdala, hipocampo e córtex pré-frontal de ratos submetidos a aquisição e extinção do medo condicionado: possíveis alvos terapêuticos do extrato padronizado de Ginkgo biloba
• Beneficiário: Suzete Maria Cerutti
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/01875-0 - Síntese paralela, screening in vitro e estudos de relação estrutura-atividade de nitroderivados ativos contra patógenos infectantes de macrófagos: Mycobacterium tuberculosis formas NRP e Leishmania sp
• Beneficiário: Daniela Goncales Galasse Rando
• Modalidade de apoio: Auxílio à Pesquisa - Regular