Efeito do tipo antidepressivo de uma 1,2,3-triazol-acetofenona em camundongos: evidências do envolvimento do sistema serotoninérgico

Abstract

Depression is a psychiatric disorder that affects millions of people. Despite the existence of various classes of antidepressants, a large proportion of depressed individuals do not experience symptom relief with treatment, highlighting the need for the development of new antidepressants. In recent years, N-heterocyclic triazole compounds have been studied for their interesting pharmacological properties, such as anti-inflammatory, anticonvulsant, and antidepressant effects. 1,2,3-triazoles have been shown to have similar mechanisms to those found in known antidepressants used as first-line treatments for depression. Based on this, novel hybrid molecules of 1,2,3-triazole-acetophenones were synthesized and their inhibition activity of monoamine oxidase (MAO) was evaluated in silico and in vitro,. Based on the data obtained, we selected the molecule with the most promising results to proceed with evaluating its antidepressant-like activity in in vivo studies. The objective of this study was to evaluate the antidepressant-like effect of 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone (ETAP), a hybrid compound containing 1,2,3-triazole and acetophenone, in mice, using two behavioral tests for evaluating depressive-like behavior: the forced swim test and tail suspension test. To evaluate the antidepressant effect of ETAP (0.5, 1, and 5 mg/kg, i.g.), it was administered 30 minutes before the behavioral tests to evaluate depressive-like behavior, and it showed an increase in the latency time for the first episode of immobility with a reduction in the total immobility time, characterizing the antidepressant-like effect. In addition to this effect, the study aimed to evaluate the involvement of the serotonergic system in the antidepressant-like action of ETAP. To evaluate the contribution of this system, we assessed the need for an intact system for the antidepressant-like action of ETAP by pretreating the mice with p-chlorophenylalanine, an enzyme inhibitor responsible for converting tryptophan to serotonin. Our results showed that the antidepressant-like effect of ETAP is serotonin dependent. We also evaluated the involvement of the receptors of this system in this effect. For this, specific antagonists of serotonin receptors, WAY100635, ketanserin, ondansetron, and GR113808, were pre-administered to evaluate the involvement of 5-HT1A, 5- HT2A/2C, 5-HT3, and 5-HT4 receptors, respectively. Our analyses showed involvement of 5-HT2A/2C and 5-HT4 receptors in the antidepressant-like effect of ETAP. Prior to the behavioral tests evaluating depressive-like behavior, the open field test was performed to exclude a possible locomotor deficit in the animals with ETAP treatment. The results demonstrate that the administration of ETAP does not alter the locomotor and exploratory activities of the animals. Additionally, the toxicity of ETAP was evaluated, and we demonstrated that treatment with this molecule did not show signs of toxicity. Thus, this study identified a new drug with potential antidepressant effects for the development of therapeutic strategies for depression.