Atividade do tipo ansiolítica do 3-((4- metoxifenil)selanil)-2- fenilbenzofurano (SeBZF3) em camundongos: uma possível contribuição do sistema serotoninérgico

Abstract

Anxiety has become one of the main disorders linked to disability and mortality. Anxiety disorders are the most frequent psychiatric conditions in the world's population. Brazil is ranked fourth among Latin countries in terms of the prevalence of anxiety disorders. Selenium-based compounds are interesting from a pharmacological point of view, as they are being related to the treatment and modulation of mental disorders in preclinical studies. Our study aimed to find some potential anxiolytic-like efficacy candidate among the class of selanyl-benzo[b]furans (SeBZF1-5). SeBZF3 stood out as an anxiolytic-like effect in the light-dark test (LDT) at a dose of 50 mg/kg performed in male Swiss mice. Thus, the mice were orally pretreated with SeBZF3 (5, 25 and 50 mg/kg, orally) or vehicle 30 min before the tests. The compound demonstrated anxiolytic-like effects in LDT and novelty suppressed feeding test (NSFT) at a dose of 50 mg/kg, while in the elevated plus maze test (EPMT) significant effects were observed from of the 25 mg/kg dose. The open field test (OFT) was also performed, aiming to rule out any psychostimulant or sedative effect of the treatments, thus, it was noticed that locomotor and exploratory parameters were not affected. Focusing on serotonergic mechanisms, in vivo experiments were designed to combine SeBZF3 treatment with central serotonin depletion or serotonergic drugs. The anxiolytic effect of SeBZF3 (50 mg/kg, i.g.) was blocked by pretreatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100 mg/kg, i.p. for 4 days). In addition, experiments were performed to investigate the combination of subeffective doses of SeBZF3 (5 mg/kg) with subeffective doses of fluoxetine (selective serotonin reuptake inhibitor, 5 mg/kg) or buspirone (5-HT1A receptor partial agonist, 2 mg/kg) in the EPMT. Repeated treatment with SeBZF3 (1 and 5 mg/kg, i.g.) was effective in causing anxiolytic-like effects. In addition, the ability of the compound to inhibit the activity of brain monoamine oxidase A (MAO A), an enzyme that preferentially degrades serotonin, was evaluated. Co-administration of subeffective doses of 11 SeBZF3 and fluoxetine or buspirone had some synergistic effects evidenced by increased time spent in the open arms and number of head dips in the EPMT. In vitro results showed that SeBZF3 (50 to 500 μM) inhibited brain MAO-A activity. The activity of this isoform was also inhibited 4 hours after oral administration of the compound, as verified by ex vivo analyses. Furthermore, the 5 mg/kg dose of SeBZF3 when administered repeatedly was effective in inhibiting the enzyme in ex vivo analyses. Taken together, these data demonstrate the anxiolytic-like effects of SeBZF3 in mice and suggest a possible involvement of the serotonergic system, however further studies are needed to elucidate further mechanisms involved in modulating the compound.