Efeito tipo antidepressivo da benzamida N-(3-(fenilselenil)prop-2-in-1-ílica (SePB) em camundongos: implicações no sistema dopaminérgico

Abstract

Owing to their complexity and heterogeneity, depressive disorders present significant challenges to conventional treatments, highlighting the need for therapeutic innovations in this area. N-(3-(phenylselenyl)prop-2-in-1-yl (SePB) has been the subject of preclinical studies owing to its antidepressant-like effects, as demonstrated in mice. Although the serotonergic influence on this effect has already been demonstrated, other transmission systems associated with DDs, such as the dopaminergic and the noradrenergic systems, have not yet been investigated. This study sought to deepen the understanding of the mechanism underlying the antidepressant-like effect of SePB using the tail suspension test (TSC) to investigate the involvement of the dopaminergic and noradrenergic systems. Additionally, the in silico pharmacokinetic profile of SePB was evaluated. Administration of dopaminergic antagonists (sulpiride 50 mg/kg, intraperitoneal injection, a selective D2/3 receptor antagonist; SCH23390 0.01 mg/kg, subcutaneous route, a D1 receptor antagonist; and haloperidol 0.05 mg/kg/kg, intraperitoneal injection, a non-selective dopamine receptor antagonist) before the administration of SePB (10 mg/kg, intragastric) prevented the anti-immobility effect demonstrated by SePB in the TSC, highlighting the involvement of these receptors in the antidepressant-like effect of SePB. Meanwhile, pre-administration of noradrenergic antagonists (prazosin 1 mg/kg, i.p., an α1-adrenergic antagonist; yohimbine 1 mg/kg, i.p., an α2-adrenergic antagonist; and propranolol 2 mg/kg, i.p., a β-adrenergic antagonist) and SePB (10 mg/kg) did not block the antidepressant-like effect observed in TSC, suggesting that noradrenergic receptors do not contribute to the therapeutic action demonstrated by SePB. Co-administration of SePB and bupropion (a norepinephrine/dopamine reuptake inhibitor) at ineffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects, corroborating previous results and demonstrating that the dopaminergic system appears to be implicated in the antidepressant-like effect of SePB. The pharmacokinetic profile of SePB demonstrated good oral bioavailability and low toxicity, suggesting its viability as a potential drug candidate. These results suggest that the mechanism of action of SePB, a novel compound with antidepressant-like effects, is related to modulation of the dopaminergic system and may represent a new pharmacological alternative to be explored in DDs.