Modulating monoaminergic systems: A study on 3,5-dimethyl-1-phenyl-4-(phenylselenyl)-1H-pyrazole in lipopolysaccharide-induced depressive-like symptoms in mice

This study investigated 3,5-dimethyl-1-phenyl-4-(phenylselenyl)-1H-pyrazole (SePy) antidepressant-like potential using in vivo, ex vivo, and in silico approaches and evaluated its hepatic and renal safety profile. Male Swiss mice received lipopolysaccharide (LPS 0.83 mg/kg, intraperitoneally) and were treated with SePy (10 mg/kg, i.g.) 24 h later. Antidepressant-like activity was evaluated using the tail suspension test (TST) and forced swimming test (FST). Monoamine oxidase (MAO) activity was subsequently measured in the prefrontal cortex, hippocampi, and small intestine to investigate previously unexplored mechanistic pathways. SePy significantly reduced immobility time in both tests (TST and FST) and inhibited MAO-A and MAO-B activities in all regions analyzed. In silico docking indicated high affinity of SePy for catalytic residues of both MAO isoforms, comparable to the reference inhibitor isocarboxazide. Toxicological analysis of SePy (5–300 mg/kg) in female mice revealed no significant hepatic alterations (alanine and aspartate aminotransferase), although elevated urea and creatinine levels suggest possible renal effects at higher doses. Taken together, the results suggest that SePy may exert antidepressant-like effects via monoaminergic modulation and displays a favorable hepatic safety profile. Additional studies are warranted to confirm its renal safety and further explore its pharmacological potential under inflammatory conditions.