Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways.

Sepsis-associated encephalopathy (SAE) remains a major unmet clinical need, due to the lack of effective treatments. Although glutathione (GSH) is known for its antioxidant properties, its specific neuroprotective role via modulation of inflammatory pathways in SAE remains poorly understood. Using a lipopolysaccharide (LPS)-induced murine sepsis model, we examined GSH's effects through comprehensive behavioral assessments, histopathological analysis, and molecular profiling. Mice were pretreated with GSH prior to LPS challenge, and outcomes were assessed across multiple parameters. This study reveals that GSH pretreatment significantly improved survival rates by 10% (p < 0.01) and significantly alleviates neurological deficits in a murine model of sepsis. Behaviorally, GSH reversed depression-like symptoms, boosting locomotor activity (p = 0.009) and reducing immobility (p < 0.05). Histopathological analysis showed that GSH preserved hippocampal structure, maintaining 40% more viable neurons in CA1/DG regions (p < 0.05). Mechanistically, GSH exerts dual neuroprotective actions: it robustly suppresses NF-κB signaling via inhibition of p65 nuclear translocation and downregulation of IL-1β and IL-6, while simultaneously activating the PKA/CREB pathway revealing a previously unrecognized mechanism of action. This study provides the first evidence of GSH's dual mechanism action in SAE, establishing it as a promising multi-target therapeutic candidate. These findings open new avenues for developing effective SAE interventions targeting both inflammatory and neuroprotective pathways.