Antidepressant-like Properties of a Selenium-Containing Pyridinium Salt Explored through In Vitro, In Vivo, and In Silico Approaches

Selenium (Se) compounds have demonstrated antioxidant and antidepressant-like effects; however, most reported molecules are highly lipophilic. In contrast, moderate water solubility is considered crucial for drug delivery and therapeutic application. Accordingly, Se-containing pyridinium salts emerge as promising candidates for depression treatment. In this study, we conducted a comprehensive evaluation of three Se-based pyridinium salts (designated as compounds <b>3A</b>, <b>3B</b>, and <b>3C</b>) using in vitro, in vivo, and in silico approaches. All three compounds exhibited cerebral antioxidant activity, significantly reducing lipid peroxidation and protein carbonylation in vitro. They also demonstrated in vitro inhibition of monoamine oxidase A and B in mouse brain tissue. Subsequently, an in vivo investigation with the salts using the tail suspension test in male Swiss mice (single intragastric dose of 5 mg/kg) identified compound <b>3B</b> as the most effective antidepressant-like agent. Further dose-response (0.5-5 mg/kg) and time-response (15-120 min) analyses established that the minimum effective dose was 1 mg/kg administered over 30 min. In silico ADMET predictions indicated favorable pharmacokinetic properties, and an acute oral toxicity study revealed that a 50-fold higher dose (50 mg/kg) than the therapeutic level did not produce any observable adverse effects. Taken together, these findings suggest that compound <b>3B</b> represents a promising antidepressant candidate for future studies.