Molecular neurobiologyApr 25, 2026

Avanafil's potential to treat inflammation-related depression and autoimmune liver disease by balancing immune and antioxidant pathways in the gut, brain, and liver

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 26, 2026

Abstract

Avanafil (AVA) treatment significantly improved behavioral performance in a rat model of inflammation-driven major depressive disorder (MDD) and autoimmune hepatitis (AIH).

LPS administration caused cognitive impairment, depressive-like symptoms, and elevated levels of pro-inflammatory cytokines.
AVA treatment enhanced gut and blood-brain barrier integrity by increasing zonula occludens-1 (ZO-1) expression.
AVA reduced levels of matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) induced by LPS.
The mechanism of action for AVA involved downregulation of the TLR4/NF-κB/IDO pathway and restoration of serotonin levels.
AVA activated the Nrf2/HO-1 signaling cascade, indicating potential effects on oxidative stress.

Simplified

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.

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Declarations. Ethical Approval: The study’s experimental procedures were authorized by the institutional animal ethics committee (Committee reference number: RECCLAR11). Euthanasia was carried out following the American Veterinary Medical Association (AVMA) Guidelines for the Euthanasia of Animals (2020). The study was conducted and reported in accordance with the ARRIVE guidelines (PLoS Biol 8(6), e1000412, 2010). Competing interests: The authors declare no competing interests.

PubMed

Avanafil's potential to treat inflammation-related depression and autoimmune liver disease by balancing immune and antioxidant pathways in the gut, brain, and liver

Abstract

Full Text

Funding

Competing interests

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