Hydroalcoholic Extract of <i>Ferula aucheri</i> Shows Anti-depressant Effect Against Lipopolysaccharide-Induced Depression in Mice: Involvement of NF-κB and TLR4 Signaling Pathway

Abstract

Background: Depression is one of the most common neuropsychiatric disorders worldwide. Lipopolysaccharide (LPS), a bacterial endotoxin, induces depressive-like behaviors by activating microglia and promoting the release of pro-inflammatory mediators, including nitric oxide, eicosanoids, and various cytokines. Owing to its rich content of flavonoids, phenolic compounds, and terpenoids, Ferula aucheri possesses potent antioxidant and anti-inflammatory properties, which may contribute to its potential as an alternative treatment for depression. Objectives: This study aimed to evaluate the antidepressant-like effects of the hydroalcoholic extract of F. aucheri on LPS-induced depression in mice. Methods: After preparation of the hydroalcoholic extract of F. aucheri, 30 mice were randomly divided into five groups: (1) Control; (2) LPS (1 mg/kg, i.p.); (3) LPS+fluoxetine (20 mg/kg, i.p.); (4) LPS+F. aucheri extract (100 mg/kg, i.p.); and (5) LPS+F. aucheri extract (200 mg/kg, i.p.). Lipopolysaccharide was administered to induce depressive-like behaviors, and after 24 hours, behavioral assessments were conducted using the forced swim test (FST), tail suspension test (TST), and open field test (OFT). Subsequently, immunohistochemical analysis was performed to assess the expression of toll-like receptor 4 (TLR4) and NF-κB in the brain tissue. Results: The FST and TST results revealed that treatment with F. aucheri extract significantly reduced immobility time compared to the LPS group, particularly at the 200 mg/kg dose, which showed superior efficacy even compared to fluoxetine. The OFT confirmed that the observed behavioral changes were not due to alterations in locomotor activity. Immunohistochemical analysis revealed that LPS significantly increased the expression of TLR4 and NF-κB in the brain. Notably, treatment with F. aucheri (200 mg/kg) significantly attenuated the expression of both biomarkers compared to the LPS group (#P < 0.05 and ##P < 0.01, respectively). Conclusions: The findings suggest that F. aucheri exhibits antidepressant-like effects in an LPS-induced model of depression, potentially mediated through modulation of neuroinflammatory pathways involving TLR4 and NF-κB. Given its promising preclinical efficacy and mechanistic relevance, F. aucheri could be considered an appropriate candidate for future clinical investigations as an antidepressant agent.