SIRT2对脓毒症小鼠远期抑郁的影响及其机制研究

Effect of SIRT2 on Long-term Depression in Mice with Sepsis and Related Mechanism

目的探讨沉默信息调节基因2(SIRT2)对脓毒症小鼠远期抑郁的影响及其机制。方法腹腔注射内毒素(LPS)制备脓毒症小鼠模型,实验动物随机分成3组:对照组(Control)、脓毒症组(LPS)、干预组(AGK2+LPS)。通过悬尾实验、强迫游泳实验和糖水偏好实验来评估小鼠抑郁状况,Western blot法检测小鼠脑内海马组织SIRT2和乙酰化核因子-κB(NF-κB)蛋白表达,免疫荧光法检测小鼠脑内海马组织Iba1活性,ELISA法测定海马组织肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)水平。结果脓毒症小鼠远期出现明显的抑郁相关表现,脑组织SIRT2蛋白表达水平降低,乙酰化NF-κB p65蛋白表达明显增加,小胶质细胞活化增加,脑组织内TNF-α和IL-1β水平增加(P<0.05,P<0.01)。SIRT2特异性抑制剂AGK2抑制脑组织内SIRT2的表达(P<0.01),而且乙酰化NF-κB p65蛋白表达、小胶质细胞活化和脑组织内TNF-α和IL-1β水平均进一步增加(P<0.05,P<0.01),远期抑郁相关表现也明显加重(P<0.01)。结论在脓毒症小鼠中,SIRT2表达下降抑制NF-κB去乙酰化,进而加重大脑组织炎症反应和远期抑郁。

Objective To investigate the effect of SIRT2 on long-term depression in mice with sepsis and its mechanism.Methods The mice were randomly divided into three groups：control group,sepsis group（injected intraperitoneally with LPS）and intervention group（injected intraperitoneally with AGK2 and LPS）.The depressive status of mice was assessed by the tail suspension test,forced swim test and sugar preference test.The expression levels of SIRT2 and acetylated NF-κB protein in hippocampus tissue were detected by Western blotting.The activity of Iba1 in hippocampus tissue was measured by immunofluorescence assay.The levels of TNF-αand IL-1βin hippocampus were measured by ELISA.Results Mice with sepsis showed significant depression-related symptom.The level of SIRT2 in hippocampus tissue was decreased,and the level of acetylated NF-κB p65,the activation of microglia,and the levels of TNF-αand IL-1βin hippocampus tissue were significantly increased（P0.05,P0.01）.AGK2,selective inhibitor of SIRT2,inhibited the expression of SIRT2 in hippocampus tissue（P0.01）,and the expression of acetylated NF-κB p65 protein,the activation of microglia and the levels of TNF-αand IL-1βin hippocampus tissue were further increased（P0.05,P0.01）,and long-term depression-related symptom was significantly aggravated（P0.01）.Conclusion Reduction of SIRT2 increased the neuroinflammation and depression in mice with sepsis through inhibiting NF-κB deacetylation.