Cefuroxime combined with metronidazole alleviates sepsis-induced cognitive dysfunction.

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis characterized by cognitive dysfunction and synaptic alterations. It is well known that neuroinflammation is involved in the pathogenesis of SAE, and antibiotics remain the mainstay for the treatment of sepsis. However, whether antibiotics could improve SAE remains unclear. This study investigated the effects of combined cefuroxime and metronidazole treatment on SAE-induced cognitive impairment, focusing on inflammation and synaptic protein expression in a cecal ligation and puncture (CLP) mouse sepsis model. Our results reveal that combined cefuroxime and metronidazole treatment significantly alleviated sepsis-induced learning and memory deficits. Furthermore, administration of HDAC2 inhibitor vorinostat (SAHA) similarly attenuated sepsis-associated cognitive dysfunction. These improvements were associated with reduced neuroinflammation and restored expression of key synaptic proteins, including drebrin and synaptophysin. Additionally, the treatment normalized the dysregulated expression of TrkB, PD-1, and PD-L1, which are critical regulators of synaptic plasticity and immune responses. Collectively, this study highlights the therapeutic potential of targeting inflammation and synaptic integrity in SAE and provides a rationale for further exploring the role of antibiotics in cognitive recovery among sepsis survivors.