齐拉西酮对小胶质细胞活化的作用及其机制  

Effects and mechanisms of ziprasidone towards the activation of microglia

作　　者：孙希玲 李春波[1] 谢斌[1] 卞茜 

机构地区：[1]上海交通大学医学院附属精神卫生中心,上海200030

出　　处：《上海交通大学学报（医学版）》2015年第10期1431-1435,共5页Journal of Shanghai Jiao tong University:Medical Science

基　　金：国家自然科学基金青年项目(81101002);上海市公共卫生优秀学科带头人培养计划~~

摘　　要：目的在在体动物系统性炎症模型中探索非典型抗精神病药物齐拉西酮对脂多糖(LPS)诱导的小胶质细胞活化的作用及机制。方法雄性SD大鼠77只,随机分为动物炎症模型组(n=35)、探索药物浓度组(n=24)以及药物干预组(n=18)。动物炎症模型组分别于腹腔注射LPS后0、2、4、8、12 h将大鼠处死,以生理盐水组为对照,通过Western blotting方法检测脑纹状体诱导性一氧化氮合酶(iN OS)蛋白表达量;探索药物浓度组分为LPS组(5 mg/kg)、齐拉西酮(1、2.5、5 mg/kg)处理后注射LPS(5 mg/kg)组、舒必利(10、25、40 mg/kg)处理后注射LPS(5 mg/kg)组、对照组(相同体积DMSO,<5%),Western blotting检测不同药物浓度下纹状体部位iN OS蛋白表达量;药物干预组分为LPS组(5 mg/kg)、齐拉西酮(5 mg/kg)处理后注射LPS(5 mg/kg)组、对照组(相同体积DMSO,<5%),通过RT-PCR方法检测纹状体部位iN OS mRNA表达,Oxyblot方法检测羰基化蛋白的表达。结果 LPS(5 mg/kg)可以引起动物炎症模型组中纹状体部位小胶质细胞iN OS蛋白表达的增多,且在4 h时iN OS蛋白表达量达到最高(P<0.05);探索药物浓度组中,高剂量齐拉西酮(5 mg/kg)可以明显抑制LPS引起的纹状体部位iN OS蛋白表达(P<0.05);药物干预组中齐拉西酮(5 mg/kg)可以明显抑制LPS引起的纹状体部位iN OS mRNA以及羰基化蛋白的表达(P<0.05)。结论非典型抗精神病药物齐拉西酮可能通过抑制小胶质细胞活化关键酶iN OS及蛋白氧化产物(羰基化蛋白)的表达,对小胶质细胞的活化产生抑制作用。Objective To explore effects and mechanisms of atypical antipsychotic ziprasidone towards the activation of microglia induced by lipopolysaccharide （LPS） in the animal model of in vivo systemic inflammation. Methods A total of 77 male SD rats were randomly divided into the animal inflammation model group （n =35）, exploration of the drug concentration group （n =24）, and drug intervention group （n =18）. Rats of the animal inflammation model group were sacrificed 0, 2, 4, 8, and 12 h after being intraperitoneally injected with LPS and controls were intraperitoneally injected with the same volume of normal saline. Western blotting was adopted to detect the protein expression of inducible nitric oxide synthase （iNOS） in the corpus striatum. Rats of the exploration of the drug concentration group were divided into the LPS group （5 mg/kg）, LPS after ziprasidone treatment groups （ 1, 2.5, and 5 mg/kg）, LPS after sulpiride treatment groups （ 10, 25, and 40 mg/kg）, and control group （same volume of DMSO, 〈50/0 ）. The protein expression of iNOS in the corpus striatum was detected by the Western blotting. Rats of the drug intervention group were divided into the LPS group （5 mg/kg）, LPS after ziprasidone treatment group （5 mg/kg）, and control group （same volume of DMSO, 〈50/0 ）. RT-PCR was used to detect the mRNA expression of iNOS in the corpus striatum and Oxyblot was adopted to detect the expression of oxidative protein in the corpus striatum. Results LPS increased the expression of iNOS of microglia in the corpus striatum of the animal inflammation model group and the expression of iNOS reached the peak at 4 h after injection （ P 〈0.05） . High concentration of ziprasidone （ 5 rag/ kg） significantly inhibited the expression of iNOS in the corpus striatum of the exploration of the drug concentration group induced by LPS （P〈0. 05）. Ziprasidone significantly inhibited the mRNA expression of iNOS and the expression of oxidative protein in the corpus striamm o

关 键 词：小胶质细胞 神经炎症 齐拉西酮 诱导性一氧化氮合酶 氧化应激 

分 类 号：R749.3[医药卫生—神经病学与精神病学]