Mefenamic acid attenuates NLRP3-associated neuroinflammation and mitochondrial dysfunction and is associated with prevention of long-term cognitive impairment after sepsis.

Sepsis survivors frequently develop long-term cognitive impairment, but the mechanisms linking systemic infection to persistent brain dysfunction remain incompletely understood. Mitochondrial dysfunction and NLRP3 inflammasome activation have been implicated in sepsis-associated encephalopathy and may represent therapeutic targets. Here, we investigated whether chronic treatment with mefenamic acid (MFA), a fenamate with reported anti-inflammatory and neuroprotective properties, attenuates late neuroinflammatory, mitochondrial, and cognitive alterations in a rat model of cecal ligation and puncture. Sepsis induced persistent NLRP3 inflammasome activation, increased IL-1β and IL-18 levels, microglial reactivity, mitochondrial ROS production, mtDNA 8-oxoG accumulation, oxidative damage, impaired respiratory chain activity, and long-term spatial and aversive memory deficits. MFA treatment, particularly at 30 and 50 mg/kg, reduced inflammasome-associated inflammatory responses and mitochondrial oxidative injury, preserved respiratory chain complex activities, modulated markers of mitophagy and mitochondrial biogenesis, and improved cognitive performance. MFA also reduced amyloid-β accumulation and increased transthyretin levels, suggesting modulation of neurodegeneration-related pathways after sepsis. These findings are consistent with a protective effect of MFA against sepsis-associated long-term brain dysfunction and identify NLRP3-associated neuroinflammation and mitochondrial damage as interconnected pathways for further therapeutic investigation.