Amantadine reduces sepsis-induced brain injury via NLRP3/caspase-1 inflammasome activation.

Objectives: Sepsis, a severe consequence of infection leading to organ failure, incites damage in frequently affected brain tissue through inflammation and oxidative stress. This study aimed to assess the effectiveness of amantadine, an N-methyl-D-aspartate (NMDA) receptor antagonist, in mitigating sepsis-induced brain damage. Materials and Methods: Thirty-two Wistar albino male rats were allocated into four groups: control, LPS (lipopolysaccharide 5 mg/kg, intraperitoneal, single-dose), LPS + amantadine, and amantadine alone. Six hours post-LPS administration, rats were euthanized under anesthesia. The neutrophilic infiltration and necrosis reaction were assessed in lung tissues through histopathological analysis, while expressions of interferon-alpha (IFN-α), caspase-3 (Cas-3), and Tumor necrosis factor-alpha (TNF-α) were examined using the immunohistochemical method. Levels of biochemical total anti-oxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were evaluated via the ELISA method. IL-1β, Cas-1, NLRP3, and IL-18 were evaluated via real-time qPCR. Results: The LPS group exhibited histopathologically significant hyperemia, increased septal tissue thickness, hemorrhage, and inflammatory cell infiltrates, and increased IFN-α, Cas-3, TNF-α immunohistochemical expressions, and IL-1 beta, IL-18, NLRP3, and Cas-1, gene expressions compared to the control group. All these findings were significantly reversed with amantadine treatment. Conclusion: The pathophysiology of brain damage due to systemic inflammation is complex. Our findings suggest that amantadine reduces neuronal injury in the brain by alleviating oxidative stress and inflammation. Notably, amantadine's efficacy appears to extend beyond NMDA receptors, implicating involvement in alternative pathways, such as Cas-1 activation by the NLRP3 inflammasome.