Antidepressant-like and memory-enhancing effects of 2-phenyl-3-(phenylselanyl)benzofuran on a lipopolysaccharide-induced depression model in male mice: behavioral, biochemical, and molecular insights.

Depression is a psychiatric disorder driven, in part, by neuroinflammation and oxidative stress. Lipopolysaccharide (LPS) induces inflammation, oxidative stress, and cognitive and behavioral alterations in rodents, thereby mimicking depression. It can also trigger peripheral organ damage, such as liver dysfunction, commonly observed in chronic inflammation. 2-Phenyl-3-(phenylselanyl)benzofuran (SeBZF1) is an antioxidant organoselenium compound with antidepressant-like properties, making it a potential candidate to counteract these effects. This study investigated whether SeBZF1 pretreatment could reduce behavioral and ex vivo alterations in male Swiss mice exposed to LPS. SeBZF1 (50 mg/kg, intragastrically) or fluoxetine (20 mg/kg, intraperitoneally, i.p, positive control) was administered 30 min before LPS (0.83 mg/kg, i.p.), and behavior assessed 24 h later. SeBZF1 significantly reduced LPS‑induced immobility in the tail suspension and forced swim tests and increased grooming in the splash sucrose test, with no changes in locomotion, indicating antidepressant-like and motivational effects. SeBZF1 reduced LPS-induced spatial memory impairment in the Y-maze test. Fluoxetine confirmed the validity of the behavioral tests. Biochemical analyses revealed that SeBZF1 decreased LPS-induced redox imbalance by lowering nitrite/nitrate (plasma), restoring non-protein thiols (prefrontal cortex and hippocampus), and reducing reactive species (hippocampus). SeBZF1 reduced alanine aminotransferase activity, a liver function marker, relative to LPS. Molecularly, SeBZF1-pretreated mice did not exhibit LPS-induced upregulation of nuclear factor kappa B (NFκB), tumor necrosis factor-alpha (TNF-α), or interleukin-4 (IL-4) mRNA in the hippocampus, suggesting anti-inflammatory effects. SeBZF1 also downregulated cortical IL-4 expression. Overall, SeBZF1 demonstrated antidepressant-like, antioxidant, and anti-inflammatory effects, supporting its potential as a candidate for depression associated with neuroinflammation.