The Effect And Mechanisms Of Long-acting GLP-1 Receptor Agonist Semaglutide On Phenotypic Transition Of Microglia And Neuroinflammation On Epileptogenesis In The Rat After Status Epilepticus

Objective:To study the effect of long-acting GLP-1 agonist semaglutide on the phenotypic transformation and neuroinflammation of hippocampal microglia in rats induced by pilocarpine-induced status epilepticus and its mechanism,and to compare it with liraglutide.Methods:60 healthy adult male SD rats weighing 230-250 g were randomly divided into normal groups(NS group,n = 6),epilepsy status model group(SE group,n = 18),and liraglutide intervention group(SE + Lira group,n = 18),semaglutide intervention group(SE + Sema group,n = 18),SE group,SE + Lira group and SE + Sema group,respectively,according to different time after the successful detection of the index The points(1d,3d,7d after SE)are divided into 3 subgroups(n = 6 for each subgroup).Intraperitoneal injection of pilocarpine(30mg / kg)induced the SE model.After successful modeling,rats in the SE + Lira group were given intraperitoneal injection of liraglutide(10nmol / kg),and rats in the SE + Sema group were alternated every day.Semaglutide(10nmol / kg)was given intraperitoneally before eating,and rats in NS group and SE group were given equal volume of normal saline.The subgroups were sacrificed at 1d,3d,and 7d after SE to detect fasting tail vein blood glucose levels.Immunohistochemical methods were used to detect hippocampal M1 phenotype microglial activation markers CD68 and M2 phenotype microglial activation.The expression levels of the markers CD206,the pro-inflammatory factorTNF-α,the NF-κB signaling pathway-related factor P65,and the neuronal nuclear antigen NeuN.Results:1 There was no statistical significance in fasting tail vein blood glucose levels among rats in NS,SE,SE + Lira and SE + Sema subgroups(P> 0.05);2 Immunohistochemical results showed that there were statistically significant differences in the expression levels of TNF-α,CD68,CD206,P65 and NeuN in hippocampus among the subgroups of NS group,SE group,SE + Lira group and SE +Sema group(P <0.001);compared with NS group,the expression level of TNF-α,CD68,CD206 and P65 in hippocampus of SE group increased,while the expression level of NeuN decreased.Among them,the expression level of CD68 gradually increased with time,and the expression level of CD206 was 1d Elevated,decreased at3 d and 7d;compared with the SE group,the expression levels of TNF-α,P65 and CD68 in the hippocampus of the SE + Lira and SE + Sema groups were decreased,while the expression levels of CD206 and NeuN were increased,while The result level of the above indicators between the two is not statistically significant(P> 0.05)Conclusion:The long-acting GLP-1 receptor agonist semaglutide inhibits the conversion of microglia to the M1 phenotype and promotes the M1 phenotype to the M2 phenotype after pilocarpine-induced status epilepticus The type of microglia is transformed,thereby reducing the inflammatory response in the nervous system;both semaglutide and liraglutide play a neuroprotective role,and the two have the same effect,but semaglutide has the advantage of fewer administrations.