Study on the Mechanism of Esketamine to Improve POCD in Mice by Regulating HMGB1/MAPK Axis

Tao Jing; Liang Qisheng; Xue Yanan; Zhang Yin; Li Min; Liu Lei

Abstract：Objective By observing the regulation of high mobility group box-1(HMGB1)/mitogen activated protein kinase(MAPK)axis at different doses of esketamine,to explore the mechanism of esketamine improving POCD in mice.Methods Healthy 18-month male mice were randomly divided into different groups:control group(group C),sepsis group(LPS group),and LPS+low-dose esketamine group 5 mg/kg(LPS+S1),LPS+medium-dose esketamine group 10 mg/kg(LPS+S2),LPS+high-dose esketamine group 15 mg/kg(LPS+S3),LPS+HMGB1 inhibitor(LPS+glycyrrhizin group),LPS+medium-dose esketamine in-tervention group+HMGB1 inhibitor(LPS+S2+glycyrrhizin group),LPS+medium-dose esketamine intervention group+MAPK signa-ling pathway inhibitor group(LPS+S2+PD98095 group),and LPS+medium-dose esketamine dry Pre-group+HMGB1 inhibitor+ MAPK signaling pathway activator(LPS+S2+glycyrrhizic acid+ANS group).The Esketamine intervention group was treated with the optimal dose of Esketamine studied in Part I after the model was established.The LPS group was intraperitoneally injected with LPS 5 mg/kg,the HMGB1 inhibitor group was intraperitoneally injected with glycyrrhizic acid at a dose of 40 mg/kg,and the control group was injected with the same dose of normal saline.Open field test and water maze test were performed after treatment with different drugs,and then the mice were killed immediately and their hippocampal tissues were taken,and the interleukin-6(IL-6),inter-leukin-1(IL-1)and tumor necrosis factor-α(TNF-α)were determined by ELISA.The expression levels of HMGB1 and MAPK signaling pathway related proteins(p38 MAPK,ERK1/ERK2,JNK)in hippocampus were detected by Western Blot.Results Compared with the control group,the expression of HMGB1,p38 MAPK,ERK1/ERK2 and JNK in the LPS group was increased,and the difference was statistically significant(P<0.05).Compared with the model mice,after inhibiting the expression of HMGB1,the LPS+S2+GA group had a significant reduction in the expression of inflammatory factors(P<0.05);compared with the model mice,after inhibiting the expression of HMGB1,the escape latency time was decreased,the number of crossing the platform was in-creased,the total travel distance was increased,the residence time in the central area was increased,and the target quadrant time was increased at each time point in the LPS+S2+GA group of sepsis model mice(P<0.05).Compared with the model mice,after in-hibiting the MAPK signaling pathway,the expression of inflammatory factors in LPS+S2+PD98095 group was decreased,and the difference was statistically significant(P<0.05).Compared with the model mice,the escape latency time and other indicators of the model group were significantly different(P<0.05).Compared with the model mice,after inhibiting the expression of HMGB1 and ac-tivating the MAPK signaling pathway,the LPS+S2+GA+ANS group had a significant reduction in the expression of inflammatory factors(P<0.05);compared with the model group,the escape latency time and other indicators of the model group were better than those of the model group,and the differences were statistically significant(P<0.05).Conclusion Esketamine can improve the expression of inflammatory factors in sepsis mice to a certain extent,and the mechanism is mainly that esketamine can directly inhibit the expres-sion or activation of HMGB1 and MAPK pathways.A deeper mechanism may be that esketamine can inhibit the activation of MAPK signaling pathways by inhibiting HMGB1,thus improving the symptoms of sepsis mouse models