Effect of acetaminophen on sepsis-associated encephalopathy in mice and relationship with ferroptosis / 中华麻醉学杂志

ABSTRACT

Objective:To evaluate the effect of acetaminophen on sepsis-associated encephalopathy (SAE) in mice and the relationship with ferroptosis.Methods:A total of 160 clean-grade healthy adult male C57BL/6J mice, aged 6 weeks, weighing 22-24 g, were divided into 4 groups ( n=40 each) using a random number table method: sham operation group (Sham group), sham operation+ acetaminophen group (Sham+ APAP group), SAE group and SAE+ acetaminophen group (SAE+ APAP group). The model of SAE was established by cecal ligation and puncture in anesthetized mice.Acetaminophen 100 mg/kg was intraperitoneally injected at 1 h before the model was established in group Sham+ APAP and group SAE+ APAP.The postoperative 7-day survival rate was recorded.At 24 h after operation, brain tissues were taken for examination of the pathological changes of neurons in hippocampal CA1 region.At 24 h after establishment of the model, ultrastructure was observed with a transmission electron microscope, the contents of reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH) in hippocampus were determined by colorimetry, and the expression of glutathione peroxidase (GPX4), cystine/glutamate antiporter (xCT) and 4-hydroxy-2-nonenal (4-HNE) was determined by Western blot. Results:Compared with group Sham, the postoperative 7-day survival rate of mice was significantly decreased, contents of ROS and MDA in hippocampus were increased, GSH content in hippocampus was decreased and expression of GPX4 and xCT was down-regulated in SAE and SAE+ APAP groups, 4-HNE expression was up-regulated in group SAE ( P<0.05), and no significant change was found in the parameters mentioned above in group Sham+ APAP ( P>0.05). Compared with group SAE, the postoperative 7-day survival rate of mice was significantly increased, contents of ROS and MDA in hippocampus were decreased, GSH content in hippocampus was increased, expression of GPX4 and xCT was up-regulated and expression of 4-HNE was down-regulated in group SAE+ APAP ( P<0.05). The pathological changes in hippocampal CA1 region and damage to ultrastructure of hippocampal tissue were significantly attenuated in group SAE+ APAP as compared with group SAE. Conclusion:Acetaminophen can effectively alleviate SAE, and the mechanism is related to inhibiting ferroptosis in mice.