The ligand-gated ion channel P2X7 receptor mediates NLRP3/caspase-1-mediated pyroptosis in cerebral cortical neurons of juvenile rats with sepsis

•Role of P2X7 receptor in sepsis-associated encephalopathy (SAE) unclear.•Increased expression of P2X7 and ERK1/2 signaling pathway observed in SAE rats.•P2X7 receptor regulated neuronal pyroptosis and p-ERK1/2 in SAE rats.•P2X7 receptor regulated IL-1β level in SAE rats by ERK1/2 signaling pathway. Sepsis-associated encephalopathy (SAE) is a common complication of severe sepsis. Some studies have suggested that P2X7 receptors, a ligand-gated ion channel receptor subgroup activated by extracellular ATP, plays an important role in cell pyroptosis. However, the role of P2X7 receptors in the development of SAE with pyroptosis and its pathways are still unclear. In this study, we established a juvenile rat model of sepsis by cecal ligation and perforation, and showed that there was a significant increase in P2X7 receptor expression in the cortex of juvenile rats with sepsis. When the P2X7 receptor antagonist was administrated, the pyroptosis and extracellular-signal-regulated kinase (ERK) 1/2 signaling pathway were inhibited, and when the P2X7 receptor agonist was administrated, the pyroptosis and ERK1/2 signaling pathway were further activated. In addition, we also found that the administration of ERK1/2 signaling pathway inhibitor not only weakened downstream pyroptosis, but also caused the inhibition of upstream P2X7 receptor expression. In conclusion, our findings illustrated that the ligand-gated ion channel P2X7 receptor mediates NLRP3/caspase-1-related pyroptosis in cerebral cortex of juvenile rats with sepsis through ERK1/2 signaling pathway and plays a neuroprotective role.