Harpagide alleviates neuroinflammation and cognitive dysfunction in sepsis-associated encephalopathy: Association with the MMP9/NF-κB signaling pathway

Background Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, characterized by uncontrolled neuroinflammation and cognitive decline, yet no specific therapy is currently available. Harpagide, a naturally occurring iridoid glycoside, has been reported to possess anti-inflammatory and neuroprotective activities; however, its therapeutic potential in SAE remains unexplored. This study aimed to investigate whether Harpagide exerts neuroprotective effects in SAE and to elucidate the underlying molecular mechanisms. Methods A mouse model of SAE was established by intraperitoneal injection of lipopolysaccharide (LPS, 18 mg/kg). Cognitive performance was assessed using behavioral assays. Brain tissue morphology and neuronal survival were evaluated through histopathological examination. Glial cell activation and the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) were measured. Network pharmacology was employed to predict potential targets, followed by molecular docking and molecular dynamics simulations to predict binding interactions with core targets. Western blotting was performed to determine the expression levels of key proteins involved in the MMP9/NF-κB signaling pathway. Results Treatment with Harpagide significantly improved behavioral performance, ameliorated brain pathological changes, preserved hippocampal neurons, suppressed glial activation, and reduced the levels of TNF-α, IL-1β, and IL-6 in SAE mice. Network pharmacology analysis predicted four core targets: GAPDH, CASP3, MMP9, and ICAM1. Molecular docking and molecular dynamics simulations suggested stable binding between Harpagide and MMP9. Western blot analysis further showed that Harpagide treatment was associated with reduced expression of MMP9 and phosphorylated NF-κB p65 in both hippocampal and cortical tissues. Conclusions The present study demonstrates that Harpagide exerts neuroprotective effects in SAE, which are associated with mitigated neuroinflammation and reduced MMP9/NF-κB signaling, supporting its potential as a promising therapeutic candidate for this devastating condition.