Antidepressant-Like Effect of a Selenoindolizine in Mice: In Vivo and In Silico Evidence for the Involvement of the Serotonergic 5-HT_2A/C Receptors

Abstract

The monoaminergic dysfunction plays a central role in major depressive disorder (MDD), a mental disturbance associated with constant feeling of sadness and lack of interest. The available treatments do not present a desirable efficacy and some of them provoke several adverse effects. In this context, organoselenium compounds and molecules containing the indolizine nucleus have demonstrated interesting pharmacological properties, including antidepressant-like effects. In this study, the antidepressant-like effect of 2-phenyl-1-(phenylselanyl)indolizine (SeI), a selenium-containing indolizine derivative, was investigated on the forced swimming test (FST) and on the tail suspension test (TST) in male Swiss mice. The involvement of the serotonergic system in this effect was also accessed. The selenium compound SeI (10−100 mg/kg, intragastrical (i.g.)) was administered 0.5 h before the behavioral tests, and it diminished the immobility on both FST and TST experiments, which is an indication of antidepressant-like effect. No changing in the locomotor motion was observed in the open-field test (OFT). The anti-immobility effect of SeI was not altered by the preadministration of the selective serotonergic receptor antagonists ondansetron (1 mg/kg, intraperitoneally (i.p.), antagonist of 5-HT 3 receptor) and WAY100635 (0.1 mg/kg, subcutaneous route (s.c.), antagonist of 5-HT 1A receptor). In contrast, the preadministration of ketanserin (1 mg/kg, i.p., antagonist of 5-HT 2A/C receptor) blocked this effect, demonstrating that the antidepressant-like effect of SeI involves 5-HT 2A/C . In addition, molecular docking studies showed a strong interaction between SeI and the receptors of 5-HT 2A and 5-HT 2C . The toxicological results demonstrated that SeI has low potential to cause adverse effects in mice. It was found that the antidepressant-like effect of SeI is related to modulation of the serotonergic system, and this selenium compound could be included in new treatment approaches for MDD.

Antidepressant-like Effect of 1-(2-(4-(4-Ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one in Mice: Evidence of the Contribution of the Serotonergic System

“…The pharmacological action of ETAP was only evaluated in male mice. The choice of only one sex for the investigation of the antidepressant-like effect of ETAP was based on the literature − that demonstrates the evaluation of pharmacological properties of candidates for new drugs being tested more frequently in male animals, presenting good reproducibility. However, we intend to expand this research to female animals in future studies.…”

“…The experimental design for constructing the dose–response curve can be seen in Figure . The pretreatment time of 30 min with ETAP was based on previous studies. ,, Each animal was used only once in each test. The tests were observed by a blinded investigator.…”

“…The doses and treatment time of each serotonin receptor antagonist used were based on previous studies (Figure ). ,, …”

Development of MAO-A and 5-HT2AR Dual Inhibitors with Improved Antidepressant Activity

“…Depression is a major public health problem, ranking the third leading cause of the global burden of disease and WHO predicts that the disorder will rank first by 2030 . Despite many progresses in the development of antidepressants, the clinical use of currently available treatments for depression are limited, as they are not always effective and cause various adverse effects . Thereby, searching for new therapeutic alternatives to treat this mental disorder more effectively and work faster and safer is an urgent need.…”

“…1 Despite many progresses in the development of antidepressants, the clinical use of currently available treatments for depression are limited, as they are not always effective and cause various adverse effects. 2 Thereby, searching for new therapeutic alternatives to treat this mental disorder more effectively and work faster and safer is an urgent need. Multiple hypotheses are developed so far to explain the genesis of depression, where the monoamine neurotransmitter is the most accepted one and is the cornerstone of the pathogenesis.…”