硫化氢抑制NLRP3炎症小体活化和炎症反应改善APP/PS1小鼠认知功能  

H2S ameliorates cognitive function in APP/PS1 mice via inhibition of NLRP3 inflammasome activation and inflammatory response

作　　者：陈君 赵富生[1] 武杨 侯广玉[1] 朱梅[1] 石莉莉 武庚 CHEN Jun(Mudanjiang Medical University,Mudanjiang 157011,China)

机构地区：[1]牡丹江医学院基础学院,黑龙江牡丹江157011 [2]牡丹江医学院附属红旗医院,黑龙江牡丹江157011 [3]牡丹江医学院第一临床医学院,黑龙江牡丹江157011

出　　处：《牡丹江医学院学报》2023年第1期1-5,20,共6页Journal of Mudanjiang Medical University

基　　金：黑龙江省中医药管理局中医药项目(ZHY18-167);黑龙江省卫生健康委科研项目(2019-383);牡丹江市应用技术研究与开发计划项目(HT2020JG053);黑龙江省大学生创新创业训练项目(201910229051)。

摘　　要：目的观察硫化氢(hydrogen sulfide,H_(2)S)对β-淀粉样前体蛋白/早老素1(amyloid precursor protein/presenilin1,APP/PS1)阿尔茨海默病(Alzheimer’s disease,AD)模型小鼠认知功能的影响,并探讨其可能的机制。方法选取24只8月龄雄性APP/PS1双转基因小鼠,随机分为APP/PS1组(腹腔注射生理盐水)和APP/PS1+NaHS(H_(2)S供体)组(腹腔注射NaHS溶液);将24只8月龄雄性C57BL/6J小鼠随机分为WT组(腹腔注射生理盐水)和WT+NaHS组(腹腔注射NaHS溶液)。采用Morris水迷宫实验检测小鼠空间学习记忆能力,尼氏染色观察神经元形态学变化,免疫荧光染色检测NOD样受体3(nod-like receptor protein3,NLRP3)分布及表达情况,ELISA法检测肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的含量,Western blot检测神经元特异性核蛋白(neuron-specific nuclear protein,NeuN)和突触素(synaptophysin,SYP)蛋白表达。结果与WT组相比较,APP/PS1组小鼠逃避潜伏期延长,平台穿越次数明显减少(P<0.05);NLRP3表达显著增加(P<0.05),TNF-α、IL-1β和IL-6含量明显升高(P<0.05);尼氏体密度、NeuN和SYP蛋白表达水平降低(P<0.05)。与APP/PS1组比较,APP/PS1+NaHS组小鼠逃避潜伏期缩短,平台穿越次数增加(P<0.05);NLRP3及促炎因子TNF-α、IL-1β和IL-6含量显著降低(P<0.05);尼氏体密度、NeuN和SYP表达水平明显升高(P<0.05)。结论H_(2)S能够改善APP/PS1小鼠认知功能,其作用机制可能与抑制NLRP3炎症小体激活,抑制神经炎症反应,减轻神经元损伤有关。Objective To observe the effect of hydrogen sulfide(H_(2)S)on the cognitive function ofβ-amyloid precursor protein/presenilin1(APP/PS1)Alzheimer’s disease(AD)model mice and explore its possible mechanism.Methods Twenty four 8-month-old male APP/PS1 double-transgenic mice were randomly divided into APP/PS1 group and APP/PS1+NaHS(H_(2)S donor)group,and 24 C57BL/6J male mice were divided into WT group and WT+NaHS group.Morris water maze test was used to detect the learning and memory and spatial exploration ability of mice.Nissl staining was used to observe morphological changes of neurons,immunofluorescence staining was used to detect the distribution and expression of NOD-like receptor 3(NLRP3),and the contents of TNF-α,IL-1βand IL-6 were detected by ELISA.Western blot was used to detect of neuron-specific nuclear protein(NeuN)and synaptophysin(SYP)proteins expression.Results Compared with the WT group,the escape latency of mice in the APP/PS1 group was prolonged,and the number of platform shuttles was significantly decreased(P<0.05);the level of NLRP3 was increased,and the contents of TNF-α,IL-1βand IL-6 were markedly increased(P<0.05);the density of Nissl bodies,the protein expression levels of NeuN and SYP were significantly decreased(P<0.05).Compared with the APP/PS1 group,the escape latency of mice was shortened,and the number of platform shuttles was increased in the APP/PS1+NaHS group(P<0.05).Moreover,the NLRP3 and the pro-inflammatory factors were decreased,while the density of Nissl body,and the levels of NeuN and SYP were increased(P<0.05).Conclusion H_(2)S can improve cognitive function in AD mice,and its mechanism of action might be related to inhibiting NLRP3 inflammasome activation,reducing inflammatory response and protecting neurons.

关 键 词：硫化氢 阿尔茨海默病 NLRP3炎症小体 认知能力 β-淀粉样前体蛋白/早老素1小鼠 

分 类 号：R459.9[医药卫生—治疗学]