Effect and its mechanism of glycyrrhizin combined with esketamine on perioperative neurocognitive disorders in mice
Objective To explore the effect and its mechanism of glycyrrhizin combined with esketamine on perioperative neurocogni-tive disorders(PND)in mice by modulating the high mobility group protein B1(HMGB1)signaling pathway in the hippocampus.Methods The mice were divided into blank group,PND group,glycyrrhizin group,esketamine group,and glycyrrhizin+esketamine group,with 24 mice in each group.The spatial learning and memory ability of mice was assessed by Morris water maze,and the escape latency was recorded in the positioning navigation experiment at day 1 before operation and at day 1,3,7 after operation,and the number of target quadrant shuttles was recorded in the spatial probe test at day 7 after operation.ELISA was used to detect the levels of interleukin-1β(IL-1β),tumour necrosis factor-α(TNF-α),HMGB1,Toll-like receptor 4(TLR-4),and nuclear factor-κB(NF-κB)in hippocampus of the mice in each group at day 1 before operation and at day 1,3,7 after operation.Immunofluorescence was performed to detect the expression of HMGB1 in the hippocampus of mice in blank group,PND group,and glycyrrhizin+esketamine group at day 1 after operation.Results There was no significant difference in all indexes among the groups at day 1 before operation(P>0.05).Morris water maze test showed that compared with blank group,the escape latency in the other groups was prolonged at the same time point after operation(P<0.05),and the number of crossing the platform at day 7 after operation was significantly decreased(P<0.05).Compared with PND group,the escape latency was shortened in glycyrrhizin group,esketamine group and glycyrrhizin+esketamine group at the same time point after operation(P<0.05),and the number of crossing the platform was increased at day 7 after operation(P<0.05).Compared with glycyrrhizin group and esketamine group,the escape latency was shortened in glycyrrhizin+esketamine group at the same time point after operation(P<0.05),and the number of crossing platforms was increased at day 7 after operation(P<0.05).ELISA results showed that compared with blank group,the expression levels of IL-1β,TNF-α,HMGB1,TLR-4 and NF-κB in the hippocampus at the same time point after operation were significantly increased in the other groups(P<0.05).Compared with PND group,the expression levels of IL-1β,TNF-α,HMGB1,TLR-4 and NF-κB were significantly decreased in the hippocampus in glycyrrhizin group,esketamine group and glycyrrhizin+esketamine group at the same time point after operation(P<0.05).Compared with glycyrrhizin group and esketamine group,the expression levels of IL-1β,TNF-α,HMGB1,TLR-4 and NF-κB were significantly decreased in the hippocampus in glycyrrhizin+esketamine group at the same time point after operation(P<0.05).Immu-nofluorescence results showed that compared with blank group,the expression of HMGB1 in the hippocampus CA1 and DG regions was significantly increased in PND group at day 1 after operation,and HMGB1 expression was detected in the cytoplasm in both hippocampus CA1 and DG regions.Compared with PND group,the expression of HMGB1 was significantly decreased in the hippocampus CA1 and DG region of mice in glycyrrhizin+esketamine group at day 1 after operation.Conclusion Glycyrrhizin combined with a subanesthetic dose of esketamine can improve the perioperative neurocognitive function and the hippocampal neuroinflammation in mice by inhibiting the HMGB1/TLR4/NF-κB signaling pathway.