1-(Phenylselanyl)-2-( <i>p</i> -tolyl)indolizine Mitigates Lipopolysaccharide (LPS)-Induced Depressive-Like Behavior by Modulating Oxidative Stress and Inflammatory Markers

1-(phenylselanyl)-2-(<i>p</i>-tolyl)-indolizine (MeSeI) is a selenoindolizine that showed antidepressant-like properties in mice via monoaminergic and glutamatergic systems. This study aimed to investigate the MeSeI effect on lipopolysaccharide (LPS)-induced depressive-like behavior in mice as well as its effect on oxidative stress parameters in primary astrocyte cultures challenged with LPS. Primary astrocyte cultures were exposed to LPS (1 μg/mL) for 3 h and treated with MeSeI (5, 10, 15, 25 μM) for 48 h. MeSeI reversed the LPS-induced increase in reactive species (RS) and nitrite levels, restored the activity of antioxidant enzymes, and increased the sulfhydryl content in astrocytes. Male <i>Swiss</i> mice received MeSeI (10 mg/kg, intragastrically) 30 min prior to LPS administration (0.83 mg/kg, intraperitoneally). After 24 h, the animals were subjected to behavioral tests and then euthanized to remove the prefrontal cortex (PFC) and plasma. MeSeI prevented LPS-induced depression-like behavior, the increase in NF-κB and IL-6 expression, and IL-6 protein levels, as well as RS levels and lipid peroxidation in the PFC, and reduced plasma corticosterone levels induced by LPS. These findings suggest that MeSeI exerts neuroprotective effects by modulating the neuroinflammatory pathway and normalizing oxidative stress parameters, indicating its potential as a therapeutic candidate for depression treatment.