Therapeutic Repurposing of Avanafil Against Lipopolysaccharide-induced Depression and Autoimmune Hepatitis: Gut-brain-liver Axis Orchestration Via Regulation of TLR4/NF-κB/IDO and Nrf2/HO-1 Pathways

Emerging evidence has highlighted the gut-brain axis as a critical mediator in the pathogenesis of both major depressive disorder (MDD) and autoimmune hepatitis (AIH), where systemic inflammation and gut barrier dysfunction play pivotal roles. This study investigated the therapeutic potential of avanafil (AVA), a selective phosphodiesterase-5 inhibitor (PDE5I), in a lipopolysaccharide (LPS)-induced rat model that mimics inflammation-driven MDD and AIH. LPS administration significantly impaired cognitive behavior, induced depressive-like symptoms, elevated pro-inflammatory cytokines, disrupted gut and blood-brain barrier (BBB) integrity, and caused hepatic dysfunction. AVA treatment markedly improved behavioral performance in the novel object recognition and forced swim test, enhanced zonula occludens-1 (ZO-1) expression, and attenuated LPS-induced elevations of matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Mechanistically, AVA downregulated the TLR4/NF-κB/IDO pathway, restored serotonin levels, reduced quinolinic acid accumulation, and activated the Nrf2/HO-1 signaling cascade in both hippocampal and liver tissues. These findings suggest that AVA exerts neuroprotective and hepatoprotective effects by modulating intestinal permeability, inflammation, and oxidative stress, making it a promising therapeutic candidate for conditions associated with systemic inflammation such as MDD and AIH.