Based On HMGB1/AMPK Pathway-mediated Mitochondrial Damage In Sepsic Encephalopathy

Research background and Objective:High mobility group box 1（HMGB1）,as a key late-stage inflammatory mediator,is involved in the pathogenesis of sepsis.Previous studies have confirmed that there is a large amount of HMGB1 in the cerebrospinal fluid of SAE patients,suggesting that HMGB1 may be involved in the pathogenesis of SAE^[1].It is closely related to cognitive dysfunction in sepsis,and the mechanism is still unclear.Sepsis associated encephalopathy（SAE）is a serious form of brain damage associated with cognitive and psychological disorders caused by sepsis,but the pathogenesis of sepsis associated encephalopathy（SAE）has not been fully elucidated.Studies have confirmed that mitochondrial injury may be the first mechanism of neurological injury in SAE^[2].Inflammatory mediators have great influence on mitochondrial function in sepsis,HMGB1 is involved in mitochondrial destruction,and AMPK is closely related to mitochondrial metabolism and energy response^[3].However,the mechanism of mitochondrial biogenesis has not been reported and studied at home and abroad.Based on this,we further studied the damage causes of SAE based on the relationship between HMGB1/AMPK pathway and mitochondrial damage.Research Method:A mouse model of sepsis was established by cecal ligation and perforation（CLP）.The success of SAE model was determined by the neurobehavioral score of mice≤6.Diammonium glycyrrhizinate（DG）was used as a HMGB1 inhibitor.They were divided into Control group（Control group）,control group+HMGB1 inhibition group（control+DG group）,operation group（SAE group）,operation group+HMGB1inhibition group（SAE+DG group）,respectively observed 6h,12h,24h after surgery,to observe the influence of each group on the neurobehavior of mice.Hematoxylin-eosin staining（HE）was used to observe the structural changes of the frontal cortex and hippocampus and the morphology of nerve cells.The level of SAE in mice was assessed by ELISA assay,and HMGB1 and AMPK expression levels were detected.Meanwhile,mitochondrial reactive oxygen species（reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,reactive oxygen species,ROS）and the changes of mitochondrial potentia（MMP）to determine the relationship between HMGB1/AMPK and mitochondrial damage.SPSS 25.0 software was used for statistical analysis.Data conforming to normal distribution were represented by（mean±standard deviation）.One-way analysis of variance between groups was used,and comparison between groups was performed in pairs.Results:1.Neurobehavioral scores of mice:Compared with Control group,neurobehavioral scores of mice at 6 h,12 h and 24 h in SAE group were significantly higher,with statistical significance（P<0.05）;with Compared with the SAE group,the neurobehavioral scores of mice in the SAE+DG group at 6h,12h and 24h were significantly decreased,with statistical significance（P<0.05）.2.Pathological changes of mouse brain tissue:24h pathological sections of mice in each group were observed and compared.It was found that the neurons in the frontal cortex,CA1,CA3 and DG regions of the brain tissue of mice in the Control group and the Control+DG group had complete structure and regular arrangement,and no obvious pathological damage was observed.Mice in SAE group had atrophy,blurred cell structure and severe pathological damage.Compared with the SAE group,the cell atrophy degree was reduced in the SAE+DG group,the cell structure was clear,and the pathological damage degree was slightly less.3.Comparison of HMGB1 and p AMPK concentrations in the hippocampus of mice in all groups:Compared with Control group,HMGB1 concentration at 6h,12h and24h in SAE group was significantly increased,while p AMPK concentration was significantly decreased,with statistical significance（P<0.05）;Compared with SAE group,HMGB1 concentration at 6h,12h and 24h in SAE+DG group was significantly decreased,and p AMPK concentration was significantly increased,with statistical significance（P<0.05）.4.Comparison of the concentration of neuron damage related marker S100β in hippocampus of mice in all groups:Compared with Control group,S100βconcentration in 6h,12h and 24h of SAE group was significantly increased,with statistical significance（P<0.05）;Compared with SAE group,S100βconcentration in SAE+DG group at 6h,12h and 24h was significantly decreased,with statistical significance（P<0.05）.5.Comparison of mitochondrial ROS and MMP in hippocampus of mice in each group:Compared with Control group,ROS concentration in 6h,12h and 24h of SAE group was significantly increased,while MMP was significantly decreased,with statistical significance（P<0.05）;Compared with SAE group,ROS concentration at 6h,12h and 24h in SAE+DG group was significantly decreased,while MMP was significantly increased,with statistical significance（P<0.05）.Conclusion:HMGB1/AMPK pathway leads to SAE by mediating mitochondrial damage,and inhibition of HMGB1 can improve mitochondrial function and reduce nervous system damage of SAE caused by this pathway.