葡萄籽原花青素对阿尔茨海默病模型大鼠学习记忆能力的改善作用及其机制研究
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摘要
目的:探究葡萄籽原花青素(GSP)对阿尔茨海默病(AD)模型大鼠学习记忆能力的改善作用及其机制。方法:将50只大鼠随机分为假手术组、模型组和GSP高、中、低剂量组(400、200、100 mg/kg),除假手术组外其余大鼠海马组织注射β-淀粉样蛋白1-42(Aβ1-42)建立AD模型,造模后48 h开始灌胃相应药物,假手术组和模型组大鼠灌胃相同体积的生理盐水,每日1次,连续给药21 d。给药14 d后采用新物体识别实验检测各组大鼠的新事物识别指数(TI);从给药16 d开始进行Morris水迷宫实验,学习5 d记录逃避潜伏期,末次给药后记录探索潜伏期和探索次数,Western blot法检测大鼠海马组织中NOD样受体蛋白3(NLRP3)的表达水平;酶联免疫吸附法检测大鼠海马组织中白细胞介素6(IL-6)、IL-1β的含量。结果:5组大鼠Morris水迷宫学习5 d内的逃避潜伏期差异均无统计学意义(P>0.05);与假手术组比较,模型组大鼠TI明显减小,探索潜伏期明显延长,探索次数明显减少,海马组织中NLRP3、IL-6、IL-1β水平均明显提高,差异具有统计学意义(P<0.05)。与模型组比较,GSP各剂量组大鼠探索潜伏期明显缩短,探索次数和TI均明显增加,海马组织中NLRP3、IL-6、IL-1β水平均明显降低,差异具有统计学意义(P<0.05)。结论:GSP可改善AD模型大鼠的记忆能力,其机制可能与抑制NLRP3炎性小体通路,减少炎症因子IL-6、IL-1β的产生有关。
OBJECTIVE:To investigate the improvement effects and its mechanism of grape seed proanthoeyanidins(GSP)on learning and memory ability of Alzheimer's disease(AD) model rats. METHODS:Totally 50 rats were randomly divided into sham operation group,model group and GSP high-dose,medium-dose and low-dose groups(400,200,100 mg/kg). Those groups were given Aβ1-42 in hippocampus of rats to establish AD model except sham operation group and given relevant medicine intragastrically 48 h after modeling. Sham operation group and model group were given constant volume of normal saline intragastrically,once a day,for consecutive 21 d. 14 d after administration,new object recognition test was adopted to test new recognition index(TI). Morris water maze test was conducted since 16 d after administration. The escape incubation period of rats were recorded 5 d during learning. Exploration incubation period and the times of exploration were recorded after last administration. Western blot was used to detect the expression of NLRP3 in rat hippocampus. ELISA was used to determine the content of IL-6 and IL-1β in rat hippocampus. RESULTS:There was no statistical significance in escape incubation period among 5 groups within 5 d of Morris water maze learning(P>0.05). Compared with sham operation group,TI of model group was decreased significantly,while exploration incubation period was prolonged significantly;the times of exploration was decreased significantly;the levels of NLRP3,IL-6 and IL-1β in hippocampus were increased significantly,with statistical significance(P<0.05). Compared with model group,exploration incubation period of GSP groups were shortened significantly,while the times of exploration and TI were increased significantly;the levels of NLRP3,IL-6 and IL-1β in hippocampus were decreased significantly,with statistical significance(P<0.05). CONCLUSIONS:GSP can improve the memory ability of AD model rats, the mechanism of which may be associated with inhibiting NLRP3 inflammatory corpuscle pathway and reducing the generation of inflammatory factors as IL-6 and IL-1β.
OBJECTIVE:To investigate the improvement effects and its mechanism of grape seed proanthoeyanidins(GSP)on learning and memory ability of Alzheimer's disease(AD) model rats. METHODS:Totally 50 rats were randomly divided into sham operation group,model group and GSP high-dose,medium-dose and low-dose groups(400,200,100 mg/kg). Those groups were given Aβ1-42 in hippocampus of rats to establish AD model except sham operation group and given relevant medicine intragastrically 48 h after modeling. Sham operation group and model group were given constant volume of normal saline intragastrically,once a day,for consecutive 21 d. 14 d after administration,new object recognition test was adopted to test new recognition index(TI). Morris water maze test was conducted since 16 d after administration. The escape incubation period of rats were recorded 5 d during learning. Exploration incubation period and the times of exploration were recorded after last administration. Western blot was used to detect the expression of NLRP3 in rat hippocampus. ELISA was used to determine the content of IL-6 and IL-1β in rat hippocampus. RESULTS:There was no statistical significance in escape incubation period among 5 groups within 5 d of Morris water maze learning(P>0.05). Compared with sham operation group,TI of model group was decreased significantly,while exploration incubation period was prolonged significantly;the times of exploration was decreased significantly;the levels of NLRP3,IL-6 and IL-1β in hippocampus were increased significantly,with statistical significance(P<0.05). Compared with model group,exploration incubation period of GSP groups were shortened significantly,while the times of exploration and TI were increased significantly;the levels of NLRP3,IL-6 and IL-1β in hippocampus were decreased significantly,with statistical significance(P<0.05). CONCLUSIONS:GSP can improve the memory ability of AD model rats, the mechanism of which may be associated with inhibiting NLRP3 inflammatory corpuscle pathway and reducing the generation of inflammatory factors as IL-6 and IL-1β.
引文
[1]RIEDERER BM,LEUBA G,VERNAY A,et al.The role of the ubiquitin proteasome system in Alzheimer’s disease[J].Exp Biol Med(Maywood),2011,236(3):268-276.
[2]CAMERON B,LANDRETH GE.Inflammation,microglia,and Alzheimer’s disease[J].Neurobiol Dis,2010,37(3):503-509.
[3]ZHANG YY,FAN YC,WANG M,et al.Atorvastatin attenuates the production of IL-1β,IL-6,and TNF-αin the hippocampus of an amyloidβ1-42-induced rat model of Alzheimer’s disease[J].Clin Interv Aging,2013,8(4):103-110.
[4]周恒,林焕冰,卓烨,等.葡萄籽原花青素对血管性痴呆大鼠空间学习记忆能力的影响[J].药学实践杂志,2011,29(3):208-211.
[5]何清,杨思雨,汪琴,等.原花青素对Aβ25-35诱导的小鼠海马神经细胞毒性的影响[J].中国临床神经科学,2014,22(5):481-488.
[6]黄雅兰,黄江,宋大强,等.积雪草苷对阿尔茨海默病模型大鼠海马组织中PAPR-γ蛋白表达的影响[J].中国药房,2016,27(34):4791-4794.
[7]HATTIANGADY B,MISHRA V,KODALI M,et al.Object location and object recognition memory impairments,motivation deficits and depression in a model of Gulf War illness[J].Front Behav Neurosci,2014.DOI:10.3389/fnbeh.2014.00078.
[8]HUANG Y,MUCKE L.Alzheimer merchanisms and therapeutic strategies[J].Cell,2012,148(6):1204-1222.
[9]张慧瑛,邢芙玲,罗光宏,等.葡萄籽原花青素抑制小鼠B16-F0黑色素瘤细胞黑色素生成的影响[J].中药药理与临床,2017,33(1):63-66.
[10]李小丽,王楷扬,胡建辉,等.葡萄籽原花青素对CCl4诱导小鼠氧化性肝损伤的保护作用及其机制研究[J].中国药房,2016,27(13):1752-1755.
[11]SCHRODER K,TSCHOPP J.The inflammasomes[J].Cell,2010,140(6):821-832.
[12]TAN MS,YU JT,JIANG T,et al.The NLRP3 inflammasome in Alzheimer’s disease[J].Mol Neurobiol,2013,48(3):875-882.
[13]HENEKA MT,KUMMER MP,STUTZ A,et al.NLRP3is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice[J].Nature,2013,493(7434):674-678.
[14]YANG CS,SHIN DM,JO EK.The role of NLR-related protein 3 inflammasome in host defense and inflammatory diseases[J].Int Neurourol J,2012,16(1):2-12.
[15]MINKIEWICZ J,RIVEROVACCARI JP,KEANE RW.Human astrocytes express a novel NLRP2 inflammasome[J].Glia,2013,61(7):1113-1121.
[2]CAMERON B,LANDRETH GE.Inflammation,microglia,and Alzheimer’s disease[J].Neurobiol Dis,2010,37(3):503-509.
[3]ZHANG YY,FAN YC,WANG M,et al.Atorvastatin attenuates the production of IL-1β,IL-6,and TNF-αin the hippocampus of an amyloidβ1-42-induced rat model of Alzheimer’s disease[J].Clin Interv Aging,2013,8(4):103-110.
[4]周恒,林焕冰,卓烨,等.葡萄籽原花青素对血管性痴呆大鼠空间学习记忆能力的影响[J].药学实践杂志,2011,29(3):208-211.
[5]何清,杨思雨,汪琴,等.原花青素对Aβ25-35诱导的小鼠海马神经细胞毒性的影响[J].中国临床神经科学,2014,22(5):481-488.
[6]黄雅兰,黄江,宋大强,等.积雪草苷对阿尔茨海默病模型大鼠海马组织中PAPR-γ蛋白表达的影响[J].中国药房,2016,27(34):4791-4794.
[7]HATTIANGADY B,MISHRA V,KODALI M,et al.Object location and object recognition memory impairments,motivation deficits and depression in a model of Gulf War illness[J].Front Behav Neurosci,2014.DOI:10.3389/fnbeh.2014.00078.
[8]HUANG Y,MUCKE L.Alzheimer merchanisms and therapeutic strategies[J].Cell,2012,148(6):1204-1222.
[9]张慧瑛,邢芙玲,罗光宏,等.葡萄籽原花青素抑制小鼠B16-F0黑色素瘤细胞黑色素生成的影响[J].中药药理与临床,2017,33(1):63-66.
[10]李小丽,王楷扬,胡建辉,等.葡萄籽原花青素对CCl4诱导小鼠氧化性肝损伤的保护作用及其机制研究[J].中国药房,2016,27(13):1752-1755.
[11]SCHRODER K,TSCHOPP J.The inflammasomes[J].Cell,2010,140(6):821-832.
[12]TAN MS,YU JT,JIANG T,et al.The NLRP3 inflammasome in Alzheimer’s disease[J].Mol Neurobiol,2013,48(3):875-882.
[13]HENEKA MT,KUMMER MP,STUTZ A,et al.NLRP3is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice[J].Nature,2013,493(7434):674-678.
[14]YANG CS,SHIN DM,JO EK.The role of NLR-related protein 3 inflammasome in host defense and inflammatory diseases[J].Int Neurourol J,2012,16(1):2-12.
[15]MINKIEWICZ J,RIVEROVACCARI JP,KEANE RW.Human astrocytes express a novel NLRP2 inflammasome[J].Glia,2013,61(7):1113-1121.