红景天苷对Aβ_(1～40)所致AD模型大鼠认知障碍的干预作用及其机制研究
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摘要
阿尔兹海默病(Alzheimer’s disease, AD)是一种以渐进性记忆减退、认知障碍及人格改变为主要临床特征的中枢神经系统退行性变性疾病。AD的病因复杂，至今尚未完全明了。人们提出了诸多假说，如淀粉级联学说、tau蛋白异常修饰学说、胆碱能神经异常学说、代谢障碍学说、自由基与凋亡学说、兴奋性氨基酸毒性学说和基因突变学说等，但均不能完全解释AD的发病机理。随着研究的不断深入，人们逐渐意识到氧化应激、炎症这些人体内广泛存在的反应与AD的发病有着密不可分的联系。
大量研究证实，β淀粉样蛋白(β-amyloid peptides, Aβ)在脑内的异常代谢和沉积是AD发病的中心环节。在Aβ刺激下小胶质细胞的活化、还原型烟酰胺腺嘌呤二核苷酸(reduced nicotinamide adenine dinucleotidephosphate，NADPH)氧化酶的激活、大量活性氧(reative oxygen species,ROS)的生成、有害自由基的产生、核因子-κB(nuclear factor-κB, NF-κB)的激活、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)及诱导型一氧化氮合酶(induced nitric oxide synthase, iNOS)等各种促炎因子的释放，都直接或间接导致了神经系统的损伤。越来越多的研究发现，在Aβ引起的一系列神经毒性作用导致神经细胞功能紊乱和死亡，并引发痴呆的进程中，脑内慢性炎症、氧化应激机制起着重要的作用。抗炎、抗氧化已成为防治AD的重要策略之一。
高原红景天为景天科红景天属(Rhodiola)植物，为我国传统的名贵藏药材。现代研究表明红景天在抗氧化损伤、清除自由基和促进细胞代谢、增强细胞活力等方面有独特功效。近年来，红景天在增强脑功能、提高记忆力方面的作用逐渐受到重视。动物实验亦表明，其在痴呆相关领域的治疗上可能具有较好的应用前景。但红景天苷作为红景天的主要有效单体，其能否对抗Aβ产生的神经损伤，能否改善AD所致认知障碍以及通过何种具体机制发挥作用迄今尚无系统深入的研究。
接受Aβ海马内注射的大鼠是较为成熟的AD模型，由于其较好地模拟了Aβ在脑内沉积的病理过程，较其它模型更为接近真实AD的进程。本研究通过建立Aβ诱导的AD动物模型，首次从行为学改变、代谢产物生成、酶学活性变化、蛋白表达激活、基因转录调控等多个层次上，较为系统地观察了红景天苷对Aβ1～40所致AD模型大鼠认知功能障碍的干预作用及其信号转导机制。
1红景天苷对Aβ1～40所致AD模型大鼠认知障碍的干预作用
目的：建立Aβ1～40诱导的AD动物模型，观察红景天苷对Aβ1～40所致认知障碍的干预作用。
方法：Aβ1～40海马内注射制备AD大鼠模型，术后用不同剂量红景天苷(25mg·kg~(-1)、50mg·kg~(-1)、75mg·kg~(-1))及石杉碱甲(0.05mg·kg~(-1))分别灌胃治疗，每日1次共21日。自第17日开始，经Morris水迷宫评测大鼠学习记忆能力，历时5日。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，组间资料应用重复测量的多因素方差分析，计数资料采用非参数的秩和检验，P<0.05为有显著性差异。
结果：(1)定位航行实验中，在测试的5日(d1～d5)内所有大鼠的逃避潜伏期都呈缩短趋势。AD模型组较假手术组逃避潜伏期明显延长(P＜0.01)。红景天苷25mg·kg~(-1)组逃避潜伏期均值较模型组有所下降，但d1、d2及d5差异均未达统计学显著性(P＞0.05)。红景天苷50mg·kg~(-1)组及75mg·kg~(-1)组逃避潜伏期各d均较模型组明显缩短(P＜0.05，P＜0.01)。石杉碱甲组大鼠逃避潜伏期较模型组明显缩短(P＜0.01)，大致介于红景天苷50mg·kg~(-1)组及75mg·kg~(-1)组之间。从d5的定位航行轨迹图可看出：假手术组大鼠游泳路线清晰、目标明确，能在较短距离内找到平台。给予Aβ海马注射的大鼠寻找目标能力减弱，游泳路线繁乱、盲目、无序，需经较长距离才能找到平台。而给予红景天苷及石杉碱甲治疗的各组大鼠找到平台前的游泳距离缩短，寻找目标的能力得到改善，其中尤以红景天苷50mg·kg~(-1)组、75mg·kg~(-1)组及石杉碱甲组改善较为显著。(2)空间探索实验中，与假手术组相比，AD模型组大鼠在原平台所在象限搜索时间所占比值明显降低(P＜0.01)，搜索过程中跨过原平台所在位置的次数也显著减少(P＜0.01)，红景天苷25mg·kg~(-1)组大鼠在原平台所在象限搜索时间所占比值及跨平台次数均较模型组有所上升，但差异均未达统计学显著性(P＞0.05)。红景天苷50mg·kg~(-1)组及、75mg·kg~(-1)组及石杉碱甲组大鼠在原平台所在象限搜索时间所占比值及跨平台次数均较模型组明显升高和增加(P＜0.01，P＜0.01)，但未恢复至正常水平。
结论：接受Aβ1～40双侧海马注射的大鼠，学习记忆能力明显下降，给予红景天苷治疗的AD大鼠，学习记忆能力的下降受到阻止。说明成功建立了Aβ1～40双侧海马注射诱导的AD大鼠模型。提示红景天苷对Aβ1～40诱导AD大鼠认知功能障碍具有改善作用。
2红景天苷对Aβ1～40所致AD模型大鼠抗氧化能力的影响目的：氧化应激是不同原因诱发神经损伤及各种中枢神经系统功能退行性紊乱的共同通路。Aβ能够通过多种途径激发脑内的氧化应激，产生大量的ROS。本实验通过观察红景天苷对Aβ1～40所致AD模型大鼠海马组织总ROS生成、血清及海马SOD活性、血清及海马MDA含量来探讨红景天苷对Aβ1～40所致AD模型大鼠脑内氧化应激损伤的影响。同时测定海马AchE活性，对比红景天苷与石杉碱甲各自优势。
方法：Aβ1～40海马内注射制备AD大鼠模型，术后给予红景天苷(50mg·kg~(-1))及石杉碱甲(0.05mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，利用DCFH-DA作荧光探针，流式细胞技术测定AD模型大鼠海马组织总ROS生成，黄嘌呤氧化酶法测定大鼠血清及海马SOD活性，硫代巴比妥酸法测定大鼠血清及海马MDA含量，三硝基苯法测定大鼠海马AchE活性。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)与假手术组相比，AD模型组大鼠海马组织ROS含量明显增加(P＜0.01)。给予红景天苷50mg·kg~(-1)·d-1治疗21日后，AD大鼠海马组织总ROS生成受到明显抑制(P＜0.01)，但未回到正常水平。给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠海马组织总ROS生成也受到明显抑制，与AD模型组相比差异达显著水平(P＜0.01)，但降低幅度不如红景天苷组。(2)与假手术组相比，AD模型组大鼠血清及海马SOD活性明显降低(P＜0.01)，给予红景天苷50mg·kg~(-1)·d-1治疗21日后，大鼠血清及海马SOD活性较AD模型组明显升高(P＜0.01)，但未回到正常水平。给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠血清SOD活性也较AD模型组明显升高，差异达显著水平(P＜0.05)，但升高幅度不如红景天苷组。(3)与假手术组相比，AD模型组大鼠血清及海马MDA含量明显升高(P＜0.01)，给予红景天苷50mg·kg~(-1)·d-1治疗21日后，大鼠血清及海马MDA含量较AD模型组明显降低(P＜0.01)，但未回到正常水平。给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠血清及海马MDA含量也较AD模型组明显降低，差异达显著水平(P＜0.05)，但降低幅度不如红景天苷组。(4)与假手术组相比，AD模型组大鼠海马AchE活性明显升高(P＜0.01)，给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠海马组织AchE活性较AD模型组明显降低(P＜0.01)，但未回到正常水平。给予红景天苷50mg·kg~(-1)·d-1治疗21日后，大鼠海马组织AchE活性也较AD模型组明显降低(P＜0.05)，但其降低幅度小于石杉碱甲组，只有石杉碱甲组的约50%。
结论：红景天苷可能通过抑制Aβ1～40诱导的AD大鼠海马组织总ROS生成、提高血清及海马SOD活性、减少血清及海马MDA含量，从局部和整体提高了AD大鼠的抗氧化能力，减轻了神经组织氧化应激损伤。红景天苷与石杉碱甲在抗氧化损伤及抑制AchE活性能力方面各自具有不同的机制和优势。
3红景天苷对Aβ1～40所致AD模型大鼠海马NADPH氧化酶-ROS通路的影响
目的：NADPH氧化酶是细胞内ROS的主要来源。本实验通过观察NADPH氧化酶的表达与激活，对红景天苷抑制AD模型大鼠海马组织ROS产生的上游机制进行探讨。
方法：Aβ1～40海马内注射制备AD大鼠模型,术后给予红景天苷(50mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，用Westernblot检测大鼠海马组织中gp91phox及p47phox蛋白表达，用RT-PCR技术检测大鼠海马gp91phox及p47phoxmRNA水平，用免疫沉淀结合Westernblot分析检测大鼠海马组织中P47phox蛋白磷酸化水平。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)Western Bolt结果显示，Aβ1～40可诱导AD模型大鼠海马组织gp9lphox及p47phox蛋白表达，使其明显升高。AD模型组两种蛋白的含量分别是假手术组的2.39倍及2.71倍(P＜0.01)。而给予红景天苷治疗后，大鼠海马组织gp9lphox及p47phox蛋白表达较AD模型组分别降低了32.6%及46.1%(P＜0.01)。(2)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织gp9lphox及p47phoxmRNA表达明显升高，分别为假手术组mRNA水平的1.99倍及2.12倍(P＜0.01)。而给予红景天苷治疗，能够明显抑制Aβ1～40的这种诱导效应。红景天苷组较AD模型组分别降低了36.5%及26.8%(P＜0.01)。(3)IP-Western Bolt结果显示，假手术组p47phox的磷酸化水平相对较低，给予Aβ1～40刺激的AD模型组p47phox磷酸化水平较高，为假手术组的5.13倍，红景天苷治疗组p47phox的磷酸化水平明显降低，较AD模型组下降了44.5%，但未回到正常水平。
结论：红景天苷能够抑制Aβphox1～40诱导的AD海马组织gp9l与p47phoxmRNA转录、蛋白表达及亚基活化。说明红景天苷抑制NADPH氧化酶产生ROS，可能是通过抑制其亚基表达和抑制其亚基激活，两者协同作用的结果。红景天苷通过对NADPH氧化酶-ROS通路的抑制，减轻了Aβ诱导的AD脑内氧化应激反应。
4红景天苷对Aβ1～40所致AD模型大鼠海马ROS-NF-κB信号通路的影响
目的：ROS的生成不但能够直接攻击神经元细胞，造成神经损伤，还可作为细胞内重要的信使，介导与活化多种信号转导通路，造成炎症反应，间接导致神经组织和细胞的损伤。NF-κB可由ROS激活，并促进多种炎性因子的转录。由Aβ-ROS-NF-κB再到下游炎性基因这条信号通路，在AD的炎性进程中具有重要的意义。本实验通过观察红景天苷对Aβ1～40所致AD模型大鼠海马ROS-NF-κB信号通路的影响，进一步揭示红景天苷抑制脑内炎性损伤的机制。
方法：Aβ1～40海马内注射制备AD大鼠模型,术后给予红景天苷(50mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，用免疫组化及Westernblot检测大鼠海马组织中NF-κB、IκBα蛋白表达，用RT-PCR技术检测大鼠海马NF-κB及IκBα mRNA水平，用Westernblot分析磷酸化NF-κB蛋白水平，用免疫沉淀结合Westernblot分析检测大鼠海马组织中IκBα蛋白磷酸化水平。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)免疫组化结果显示：假手术组大鼠海马组织内NF-κB染色阳性细胞少，着色浅。AD模型组海马组织细胞内NF-κB染色阳性细胞数明显增多，内含大量棕黄色阳性颗粒。红景天苷组阳性细胞数较AD模型组明显减少，着色变浅。Western Bolt结果亦显示，给予Aβ1～40海马注射后，AD模型组大鼠海马组织NF-κB蛋白表达较假手术组显著升高，为假手术组的2.43倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织NF-κB蛋白表达较AD模型组降低了32.9%，差异显著(P＜0.01)。(2)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织NF-κB mRNA表达明显升高，为假手术组的2.07倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织NF-κB mRNA表达较AD模型组降低了35.9%(P＜0.01)。(3)免疫组化对NF-κB蛋白的定位显示：假手术组大鼠海马组织仅有少数细胞胞浆内有NF-κB染色的棕黄色阳性颗粒，且着色浅，胞核内几乎未见染色。AD模型组海马细胞的胞浆与胞核中均可见大量棕黄色阳性颗粒分布，较假手术组明显增多，红景天苷组海马细胞的胞核中NF-κB阳性颗粒较AD模型组明显减少。IP-Western Bolt结果显示：假手术组大鼠海马组织中NF-κB的磷酸化水平相对较低，给予Aβ1～40的模型组大鼠海马组织中NF-κB磷酸化水平较高，为假手术组的4.91倍(P＜0.01)，红景天苷治疗组大鼠海马组织中NF-κB磷酸化水平明显降低，较AD模型组下降了53.5%(P＜0.01)，但未回到正常水平。(4)免疫组化结果显示：AD模型组大鼠海马组织细胞内IκBα阳性染色细胞数较假手术组明显减少，而红景天苷组IκBα阳性染色细胞数较AD模型组明显增多。Western blot结果亦显示给予Aβ1～40海马注射后，AD模型组大鼠海马组织内IκBα水平较假手术组明显下降，降幅达58.7%(P＜0.01)，给予红景天苷治疗后，大鼠海马组织IκBα水平明显回升，较AD模型组上升了99.2%(P＜0.01)。(5)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织IκBα mRNA表达明显降低，降幅达62.7%(P＜0.01)。给予红景天苷治疗后，大鼠海马IκBα mRNA表达较AD模型组升高了92.2%(P＜0.01)。(6)IP-Western Bolt结果显示，假手术组IκBα的磷酸化水平相对较低，给予Aβ1～40的模型组大鼠海马组织中IκBα磷酸化水平较高，为假手术组的2.98倍，红景天苷治疗组大鼠海马IκBα的磷酸化水平明显降低，较AD模型组下降了33.4%。
结论：一方面红景天苷通过抑制Aβ1～40诱导的NF-κB蛋白表达起到抑制ROS-NF-κB通路的作用，另一方面红景天苷通过抑制IκBα的磷酸化降解、增强IκBα的表达，起到抑制NF-κB激活进而抑制ROS-NF-κB通路的作用。这对于抑制Aβ介导的脑内炎症反应具有重要的意义。
5红景天苷对Aβ1～40所致AD模型大鼠海马iNOS及RAGE表达的影响
目的：iNOS及RAGE受到NF-κB的诱导表达后，不但自身能直接介导Aβ诱导的多种神经毒性作用，还能反过来再次激活NF-κB，放大炎性效应，造成恶性循环。本实验通过对iNOS及RAGE表达的观察，进一步探讨红景天苷对Aβ1～40所致AD模型大鼠脑内氧化应激及炎症反应的综合干预作用。
方法：Aβ1～40海马内注射制备AD大鼠模型,术后给予红景天苷(50mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，用免疫组化及Westernblot检测大鼠海马组织中iNOS及RAGE蛋白表达，用RT-PCR技术检测大鼠海马iNOS及RAGE mRNA水平。数据用ˉx±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)免疫组化结果显示：假手术组大鼠海马组织内iNOS染色阳性细胞少，着色浅。AD模型组海马组织细胞内iNOS染色阳性细胞数明显增多，内含大量棕黄色阳性颗粒。红景天苷组阳性细胞数较AD模型组明显减少，着色变浅。(2)Western Bolt结果亦显示，给予Aβ1～40海马注射后，AD模型大鼠海马组织iNOS蛋白表达较假手术组显著升高，为假手术组的3.72倍。(P＜0.01)。给予红景天苷治疗后，大鼠海马组织iNOS蛋白表达较模型组降低了47.4%(P＜0.01)。(3)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织内iNOS mRNA表达明显升高，为假手术组的2.08倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织iNOS mRNA表达较模型组降低了37.0%(P＜0.01)。(4)免疫组化结果显示：假手术组大鼠海马组织细胞内，几乎没有RAGE染色的棕黄色阳性颗粒。AD模型组海马细胞内RAGE染色阳性细胞数明显增多，红景天苷组RAGE染色阳性细胞数较AD模型组明显减少。(5)Western Bolt结果亦显示，给予Aβ1～40海马注射后，AD模型大鼠海马组织RAGE蛋白表达较假手术组显著升高，为假手术组的1.86倍。(P＜0.01)。给予红景天苷治疗后，大鼠海马组织RAGE蛋白表达较模型组降低了31.4%(P＜0.01)。(6)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织RAGE mRNA表达明显升高。为假手术组的1.65倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织RAGEmRNA表达较模型组降低了23.8%(P＜0.01)。
结论：红景天苷通过抑制Aβ1～40诱导的大鼠海马组织内NF-κB-iNOS、NF-κB-RAGE信号通路及其反馈激活，遏制了氧化应激与炎性损伤相互作用、相互促进的恶性循环，对神经组织起到综合保护作用。
Alzheimer’s disease (AD) is a chronic progressive neurodegenerativedisorder. It is characterised clinically by progressive loss of memory,cognitive dysfunction and personality changes as the three primary groups ofsymptoms. Pathogenesis of AD is complex and not fully understood yet.People proposed various hypotheses with respect to etiology of AD，such asthe amyloid hypothesis, the tau proteins hypothesis, the cholinergic hypothesis,the dysmetabolism hypothesis, the free radicals and apoptosis hypothesis, theexcitatory amino acids hypothesis, the genic mutation hypothesis, et al.However, none of them can fully explain the pathogenesis of AD. With thedevelopment of research, people have come to realized that the oxidativestress, inflammation which are widespread reactions in the body haveinseparable connection with AD.
Plenty of evidence shows that abnormal metabolism of β-amyloid (Aβ)peptides and accumulation of excessive Aβ plays a critical role in progress ofAD. Abnormal deposition of Aβ can activate microglia secreteproinflammatory molecules and cellular factors, induce nicotinamide adeninedinucleotide phosphate oxidase (NADPH oxidase) to generate reactive oxygenspecies (ROS), activate nuclear factor-κB (NF-κB), induce the expression oftumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS).These reactions exert direct or indirect injuries of nervous system. Increasingevidence demonstrates that Aβ caused a series of neurotoxic effect whichcause neuron disfunction, death and further lead to dementia. Chronicinflammation in the brain and oxidative stress played significant roles in thiscourse. Anti-inflammatory and anti-oxidative therapy has become one of themost important strategies for the prevention and treatment of AD.
Plateau rhodiola is a perennial plant of Rhodiola family. It was a traditional famous Tibetan medicine. Researches show that rhodiola havespecial effects in preventing oxidative damage, scavenging free radicals,improving cell metabolism and enhancing cell vitality. Growing attention hasbeen received on it’s benefits of enhancing the brain function and improvingmemory, in the past few years. Animal experiments also showed that rhodiolamay have good prospects in the treatment of dementia and related fields.However, salidroside as the main effective component of rhodiola, its effectand mechanism on cognitive deficit of Alzheimer’s disease is still not clearand need systematic and profound researches.
The rat received intrahippocampal injection of Aβ is a mature model forAD. This model is closer to the real pathological processes of AD than othermodels, because of its good simulation of Aβ deposition in the brain. Aim toexplore the potential effects of salidroside on cognitive impairment of AD andthe related molecular mechanism, this study established Aβ1～40induced ratsmodel of AD. Systematical investigations were first undertaken from theaspects of behavior changes, generation of metabolism products, enzymologychanges in activity, protein expression, transcriptional regulation and so on.
1The effects of salidroside on cognitive deficits of AD model rats.
Objective: To establish Aβ1～40induced rat models of AD and observethe effects of salidroside on cognitive deficits of these models.
Methods: Male SD rats were randomly divided into6groups: shamcontrol group, AD model group, salidroside in small, medium and large dose(25mg·kg~(-1),50mg·kg~(-1),75mg·kg~(-1)) groups and huperzine A group(0.05mg·kg~(-1)). Aβ1～40was injected into bilateral hippocampus to create AD model.Rats were administered by gavage with salidroside for3weeks to determinethe protective and therapeutic effects on treatment rats. Morris water mazetesting system was undertaken to observe the changes of learning and memoryabilities in rats. Data were presented as xˉ±s and analyzed with multi-variatetest of repetitive measure ANOVA using SPSS statistical program.Enumeration data were analyzed with Rank sum test. A level of P<0.05wasconsidered statistically significant.
Results:(1) The analysis of the place navigation trial showed that theescape latencies decreased from Day1to Day5in all groups. The AD modelrats displayed longer escape latencies than the rats of sham control group(P＜0.01). The animals that treated with salidroside displayed significantlylower escape latencies than those in AD model group (P＜0.01). But therewas no significant difference between salidroside(25mg·kg~(-1))-treated groupand AD model group at the day1,2and5(P＞0.05). The animals inhuperzine A group displayed significantly lower escape latencies than those inAD model group (P＜0.05). Representative navigation paths at day5oftraining demonstrated that spatial learning acquisition was impaired in theanimals of AD model group relative to animals of salidroside-treated groupand huperzine A group.(2) In the spatial probe trial, The AD model rats spentsignificantly less time in the quadrant where the platform was hidden thananimals in sham control group (P＜0.01). The number of crossings to theprevious location of the platform was decreased in AD model group relative toanimals in sham control group (P＜0.01). Animals treated with salidroside(25mg·kg~(-1)) spent more time in the target quadrant and showed moreplatform-passing times than animals in AD model group, but there was nosignificant difference between them (P＞0.05). Animals in salidroside (50mg·kg~(-1),75mg·kg~(-1)) groups and huperzine A group spent more time in thetarget quadrant and showed statistically more platform-passing times thananimals in AD model group (P＜0.01).
Conclusions: The behavioural data obtained in the Morris water mazetest demonstrate that salidroside is able to protect animals from the memoryimpairments induced by intrahippocampal injection of Aβ1～40.
2The effects of salidroside on anti-oxidative activities of AD modelrats.
Objective: To observe the effects of salidroside on the generation of totalROS, the superoxide dismutase (SOD) activity, the malondialdehyde (MDA)level and the acetylcholinesterase (AChE) activity in serum and hippocampusof AD model rats.
Methods: Male SD rats were randomly divided into4groups: sham control group, AD model group, salidroside (50mg·kg~(-1)) group and huperzineA group (0.05mg·kg~(-1)). Aβ1～40was injected into bilateral hippocampus tocreate AD model. Rats were administered by gavage with salidroside for3weeks. The generation of total ROS in hippocampus was determined by flowcytomertry technology, the superoxide dismutase (SOD) activity and themalondialdehyde (MDA) level in serum and hippocampus as well as theacetylcholinesterase (AChE) activity in serum were determined by separatebiochemical kit. Data were presented as xˉ±s and analyzed with ANOVA andLSD using SPSS statistical program. A level of P＜0.05was consideredstatistically significant.
Results:(1) The results showed animals received intrahippocampalinjection of Aβ1～40displayed a significantly enhancement of ROS productioncompared with the sham control group (P <0.01). The level of ROS wassignificantly inhibited after treated with salidroside or huperzine A incomparison with the AD model group (P <0.01, P <0.01). The inhibition ofROS by huperzine A was weaker than that by salidroside.(2) Animalsreceived intrahippocampal injection of Aβ1～40displayed a significantlydecrease of the SOD activity in serum and hippocampus compared with thesham control group (P <0.01). The SOD activity was significantly increasedafter treated with salidroside or huperzine A in comparison with the AD modelgroup (P <0.01, P <0.01). The increase of SOD activity by huperzine A wasweaker than that by salidroside.(3) Intrahippocampal injection of Aβ1～40induced significant increase of the MDA level in the serum and hippocampusof AD model group (P <0.01). On the other hand, we observed a significanttrend for decrease of the MDA level after salidroside or huperzine A treatmentin comparison with the AD model groups (P <0.01, P <0.05). The decrease ofthe MDA level by huperzine A was weaker than that by salidroside.(4) ADmodel group showed a significantly increase of the AChE activity inhippocampus compared with the sham control group (P <0.01). The AChEactivity was significantly inhibited after treated with salidroside or huperzineA in comparison with the AD model group (P <0.05, P <0.01). The inhibition of AChE activity by salidroside was weaker than that by huperzine A.
Conclusions: Salidroside could significantly decrease the generation oftotal ROS in hippocampus, increase the SOD activity in serum andhippocampus, decrease the malondialdehyde (MDA) level in serum andhippocampus and inhibit the AChE activity in hippocampus of AD model rats.These effects enhanced the anti-oxidative activities and prevented the neuronaldamage from oxidative stress. There are different mechanisms and advantagesbetween salidroside and huperzine A on the effects of preventing oxidativedamage and suppressing AchE activity.
3The effects of salidroside on NADPH oxidase-ROS signalpathway in hippocampus of AD model rats.
Objective: NADPH oxidase is the main source of ROS in cells. In thepresent study, the expression and activation of NADPH oxidase inhippocampus of AD model rats were observed in order to elucidate the signalmechanism of salidroside on the suppressing generation of ROS.
Methods: Male SD rats were randomly divided into3groups: shamcontrol group, AD model group, salidroside (50mg·kg~(-1)) group. Aβ1～40wasinjected into bilateral hippocampus to create AD model. Rats wereadministered by gavage with salidroside for3weeks. The expression level ofgp91phoxand p47phoxprotein in hippocampus of AD model rats weredetermined by Westernblot. The expression level of gp91phoxand p47phoxmRNA were assayed by means of RT-PCR. The phosphorylation level ofp47phoxprotein was detected by immuno precipitation analysis. Data werepresented as xˉ±s and analyzed with ANOVA and LSD using SPSS statisticalprogram. A level of P＜0.05was considered statistically significant.
Results:(1) Western blot analysis showed that the expression level ofgp91phoxand p47phoxprotein in hippocampus of AD model rats weresignificantly increased by2.39times and2.71times, compared with shamcontrol group (P＜0.01). After treated with salidroside the expression levelof gp91phoxand p47phoxprotein in hippocampus of salidroside group weresignificantly inhibited by32.6%and46.1%respectively, in comparison with the AD model group (P＜0.01).(2) RT-PCR analysis showed that theexpression level of gp91phoxand p47phoxmRNA in hippocampus of AD modelrats were significantly rosed by1.99times and2.12times, compared withsham control group (P＜0.01). After treated with salidroside the expressionlevel of gp91phoxand p47phoxmRNA in hippocampus of salidroside group weresignificantly reduced by36.5%and26.8%respectively, in comparison withthe AD model group (P＜0.01).(3) IP-Western Bolt analysis showed that thephosphorylation level of p47phoxprotein in hippocampus of AD model ratswere significantly increased by5.13times, compared with sham control group(P＜0.01). After treated with salidroside the phosphorylation level of p47phoxprotein in hippocampus of salidroside group were significantly inhibited by44.5%respectively, in comparison with the AD model group (P＜0.01).
Conclusions: Salidroside could significantly decrease the genetranscription and protein expression as well as the subunit activation ofNADPH oxidase. The findings indicate that both the effects of suppressingsubunits expression and inhabiting subunit activation on NADPH oxidase,decreased the level of ROS in hippocampus, further reduced the oxidativedamage.
4The effects of salidroside on ROS-NF-κB signal pathway inhippocampus of AD model rats.
Objective: It has been demonstrated that activated microglia produceROS, which may induce or exacerbate neurotoxicity by causing oxidativestress to neurons. Studies also showed that ROS production was attributable tothe activation of NF-κB and consequent pro-inflammatory cytokines.Aβ-ROS-NF-κB signal pathway has been shown to play an important role inchronic inflammation during the onset and progression of AD. In the presentstudy, the activation of ROS-NF-κB signal pathway in hippocampus of ADmodel rats was observed in order to elucidate the signal mechanism ofsalidroside on the attenuation of inflammatory damage in the brain.
Methods: Male SD rats were randomly divided into3groups: shamcontrol group, AD model group, salidroside (50mg·kg~(-1)) group. Aβ1～40was injected into bilateral hippocampus to create AD model. Rats wereadministered by gavage with salidroside for3weeks. The expression level ofNF-κB and IκBα protein in hippocampus of AD model rats were determinedby Westernblot and Immunohistochemical analysis. The expression level ofNF-κB and IκBα mRNA were assayed by means of RT-PCR. Thephosphorylation level of NF-κB protein was detected by Westernblot. Thephosphorylation level of IκBα protein was detected by immuno precipitationanalysis. Data were presented asˉx±s and analyzed with ANOVA and LSDusing SPSS statistical program. A level of P＜0.05was consideredstatistically significant.
Results:(1) Western blot analysis showed that the expression level ofNF-κB protein in hippocampus of AD model rats were significantly increasedby2.43times, compared with sham control group (P＜0.01). After treatedwith salidroside the expression level of NF-κB protein in hippocampus ofsalidroside group were significantly inhibited by32.9%respectively, incomparison with the AD model group (P＜0.01). Immunohistochemicalanalysis showed the same trend as shown in Western blot. The NF-κB positivecells were increased in AD Model group and decreased in salidroside group.(2) RT-PCR analysis showed that the expression level of NF-κB mRNA inhippocampus of AD model rats were significantly rosed by2.07timescompared with sham control group (P＜0.01). After treated with salidrosidethe expression level of NF-κB mRNA in hippocampus of salidroside groupwere significantly reduced by35.9%respectively, in comparison with the ADmodel group (P＜0.01).(3) Western Bolt analysis showed that thephosphorylation level of NF-κB protein in hippocampus of AD model ratswere significantly increased by4.91times, compared with sham control group(P＜0.01). After treated with salidroside the phosphorylation level of NF-κBprotein in hippocampus of salidroside group were significantly inhibited by53.5%respectively, in comparison with the AD model group (P＜0.01).(4)Western blot analysis showed that the expression level of IκBα protein inhippocampus of AD model rats were significantly decreased by58.7%, compared with sham control group (P＜0.01). After treated with salidrosidethe expression level of IκBα protein in hippocampus of salidroside group weresignificantly rosed by99.2%respectively, in comparison with the AD modelgroup (P＜0.01). Immunohistochemical analysis showed the same trend asshown in Western blot. The IκBα positive cells were decreased in AD Modelgroup and rosed in salidroside group.(5) RT-PCR analysis showed that theexpression level of IκBα mRNA in hippocampus of AD model rats weresignificantly reduced by62.7%compared with sham control group (P＜0.01).After treated with salidroside the expression level of IκBα mRNA inhippocampus of salidroside group were significantly increased by92.2%respectively, in comparison with the AD model group (P＜0.01).(6)IP-Western Bolt analysis showed that the phosphorylation level of IκBαprotein in hippocampus of AD model rats were significantly increased by2.98times, compared with sham control group (P＜0.01). After treated withsalidroside the phosphorylation level of IκBα protein in hippocampus ofsalidroside group were significantly inhibited by33.4%respectively, incomparison with the AD model group (P＜0.01).
Conclusions: On the one hand salidroside could inhibit the ROS-NF-κBsignal pathway by reducing the NF-κB protein expression, on the other handsalidroside could inhibit the ROS-NF-κB signal pathway by reducing thephosphorylation level of IκBα protein and enhancing IκBα protein expression,both of which can inhibit the NF-κB activation. These effects have greatsignificance for attenuating Aβ-mediated inflammation in the brain.
5The effects of salidroside on iNOS and RAGE expression inhippocampus of AD model rats.
Objective: Excessive expression of iNOS and RAGE can be induced byNF-κB. These productions can not only mediate the neurotoxicity of Aβderectly by themselves, but also activate NF-κB again, which will amplify theinflammatory effects and resulted in vicious circles. In the present study, theexpression of iNOS and RAGE in hippocampus of AD model rats wereobserved in order to further elucidate the comprehensive intervention of salidroside on the oxidative stress and inflammation in the brain.
Methods: Male SD rats were randomly divided into3groups: shamcontrol group, AD model group, salidroside (50mg·kg~(-1)) group. Aβ1～40wasinjected into bilateral hippocampus to create AD model. Rats wereadministered by gavage with salidroside for3weeks. The expression level ofiNOS and RAGE protein in hippocampus of AD model rats were determinedby Westernblot and Immunohistochemical analysis. The expression level ofiNOS and RAGE mRNA were assayed by means of RT-PCR. Data werepresented as xˉ±s and analyzed with ANOVA and LSD using SPSS statisticalprogram. A level of P＜0.05was considered statistically significant.
Results:(1) Western blot analysis showed that both the expression levelof iNOS and RAGE protein in hippocampus of AD model rats weresignificantly increased by3.72times and1.86times, compared with shamcontrol group (P＜0.01). After treated with salidroside the expression levelof iNOS and RAGE protein in hippocampus of salidroside group weresignificantly inhibited by47.4%and31.4%respectively, in comparison withthe AD model group (P＜0.01). Immunohistochemical analysis showed thesame trend as shown in Western blot. Both of the iNOS and RAGE positivecells were increased in AD Model group and decreased in salidroside group.(2) RT-PCR analysis showed that the expression level of iNOS and RAGEmRNA in hippocampus of AD model rats were significantly rosed by2.08times and1.65times compared with sham control group (P＜0.01). Aftertreated with salidroside the expression level of iNOS and RAGE mRNA inhippocampus of salidroside group were significantly reduced by37.0%and23.8%respectively, in comparison with the AD model group (P＜0.01).
Conclusions: Salidroside could inhibit the activation of NF-κB-iNOSand NF-κB-RAGE signal pathways and their feedback loop in hippocampus ofAD model rats. All of these effects might suppress the interaction and thevicious cycle from mutual promotion between oxidative stress andinflammatory damage, that would give a comprehensive protection fornervous tissue.
大量研究证实，β淀粉样蛋白(β-amyloid peptides, Aβ)在脑内的异常代谢和沉积是AD发病的中心环节。在Aβ刺激下小胶质细胞的活化、还原型烟酰胺腺嘌呤二核苷酸(reduced nicotinamide adenine dinucleotidephosphate，NADPH)氧化酶的激活、大量活性氧(reative oxygen species,ROS)的生成、有害自由基的产生、核因子-κB(nuclear factor-κB, NF-κB)的激活、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)及诱导型一氧化氮合酶(induced nitric oxide synthase, iNOS)等各种促炎因子的释放，都直接或间接导致了神经系统的损伤。越来越多的研究发现，在Aβ引起的一系列神经毒性作用导致神经细胞功能紊乱和死亡，并引发痴呆的进程中，脑内慢性炎症、氧化应激机制起着重要的作用。抗炎、抗氧化已成为防治AD的重要策略之一。
高原红景天为景天科红景天属(Rhodiola)植物，为我国传统的名贵藏药材。现代研究表明红景天在抗氧化损伤、清除自由基和促进细胞代谢、增强细胞活力等方面有独特功效。近年来，红景天在增强脑功能、提高记忆力方面的作用逐渐受到重视。动物实验亦表明，其在痴呆相关领域的治疗上可能具有较好的应用前景。但红景天苷作为红景天的主要有效单体，其能否对抗Aβ产生的神经损伤，能否改善AD所致认知障碍以及通过何种具体机制发挥作用迄今尚无系统深入的研究。
接受Aβ海马内注射的大鼠是较为成熟的AD模型，由于其较好地模拟了Aβ在脑内沉积的病理过程，较其它模型更为接近真实AD的进程。本研究通过建立Aβ诱导的AD动物模型，首次从行为学改变、代谢产物生成、酶学活性变化、蛋白表达激活、基因转录调控等多个层次上，较为系统地观察了红景天苷对Aβ1～40所致AD模型大鼠认知功能障碍的干预作用及其信号转导机制。
1红景天苷对Aβ1～40所致AD模型大鼠认知障碍的干预作用
目的：建立Aβ1～40诱导的AD动物模型，观察红景天苷对Aβ1～40所致认知障碍的干预作用。
方法：Aβ1～40海马内注射制备AD大鼠模型，术后用不同剂量红景天苷(25mg·kg~(-1)、50mg·kg~(-1)、75mg·kg~(-1))及石杉碱甲(0.05mg·kg~(-1))分别灌胃治疗，每日1次共21日。自第17日开始，经Morris水迷宫评测大鼠学习记忆能力，历时5日。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，组间资料应用重复测量的多因素方差分析，计数资料采用非参数的秩和检验，P<0.05为有显著性差异。
结果：(1)定位航行实验中，在测试的5日(d1～d5)内所有大鼠的逃避潜伏期都呈缩短趋势。AD模型组较假手术组逃避潜伏期明显延长(P＜0.01)。红景天苷25mg·kg~(-1)组逃避潜伏期均值较模型组有所下降，但d1、d2及d5差异均未达统计学显著性(P＞0.05)。红景天苷50mg·kg~(-1)组及75mg·kg~(-1)组逃避潜伏期各d均较模型组明显缩短(P＜0.05，P＜0.01)。石杉碱甲组大鼠逃避潜伏期较模型组明显缩短(P＜0.01)，大致介于红景天苷50mg·kg~(-1)组及75mg·kg~(-1)组之间。从d5的定位航行轨迹图可看出：假手术组大鼠游泳路线清晰、目标明确，能在较短距离内找到平台。给予Aβ海马注射的大鼠寻找目标能力减弱，游泳路线繁乱、盲目、无序，需经较长距离才能找到平台。而给予红景天苷及石杉碱甲治疗的各组大鼠找到平台前的游泳距离缩短，寻找目标的能力得到改善，其中尤以红景天苷50mg·kg~(-1)组、75mg·kg~(-1)组及石杉碱甲组改善较为显著。(2)空间探索实验中，与假手术组相比，AD模型组大鼠在原平台所在象限搜索时间所占比值明显降低(P＜0.01)，搜索过程中跨过原平台所在位置的次数也显著减少(P＜0.01)，红景天苷25mg·kg~(-1)组大鼠在原平台所在象限搜索时间所占比值及跨平台次数均较模型组有所上升，但差异均未达统计学显著性(P＞0.05)。红景天苷50mg·kg~(-1)组及、75mg·kg~(-1)组及石杉碱甲组大鼠在原平台所在象限搜索时间所占比值及跨平台次数均较模型组明显升高和增加(P＜0.01，P＜0.01)，但未恢复至正常水平。
结论：接受Aβ1～40双侧海马注射的大鼠，学习记忆能力明显下降，给予红景天苷治疗的AD大鼠，学习记忆能力的下降受到阻止。说明成功建立了Aβ1～40双侧海马注射诱导的AD大鼠模型。提示红景天苷对Aβ1～40诱导AD大鼠认知功能障碍具有改善作用。
2红景天苷对Aβ1～40所致AD模型大鼠抗氧化能力的影响目的：氧化应激是不同原因诱发神经损伤及各种中枢神经系统功能退行性紊乱的共同通路。Aβ能够通过多种途径激发脑内的氧化应激，产生大量的ROS。本实验通过观察红景天苷对Aβ1～40所致AD模型大鼠海马组织总ROS生成、血清及海马SOD活性、血清及海马MDA含量来探讨红景天苷对Aβ1～40所致AD模型大鼠脑内氧化应激损伤的影响。同时测定海马AchE活性，对比红景天苷与石杉碱甲各自优势。
方法：Aβ1～40海马内注射制备AD大鼠模型，术后给予红景天苷(50mg·kg~(-1))及石杉碱甲(0.05mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，利用DCFH-DA作荧光探针，流式细胞技术测定AD模型大鼠海马组织总ROS生成，黄嘌呤氧化酶法测定大鼠血清及海马SOD活性，硫代巴比妥酸法测定大鼠血清及海马MDA含量，三硝基苯法测定大鼠海马AchE活性。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)与假手术组相比，AD模型组大鼠海马组织ROS含量明显增加(P＜0.01)。给予红景天苷50mg·kg~(-1)·d-1治疗21日后，AD大鼠海马组织总ROS生成受到明显抑制(P＜0.01)，但未回到正常水平。给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠海马组织总ROS生成也受到明显抑制，与AD模型组相比差异达显著水平(P＜0.01)，但降低幅度不如红景天苷组。(2)与假手术组相比，AD模型组大鼠血清及海马SOD活性明显降低(P＜0.01)，给予红景天苷50mg·kg~(-1)·d-1治疗21日后，大鼠血清及海马SOD活性较AD模型组明显升高(P＜0.01)，但未回到正常水平。给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠血清SOD活性也较AD模型组明显升高，差异达显著水平(P＜0.05)，但升高幅度不如红景天苷组。(3)与假手术组相比，AD模型组大鼠血清及海马MDA含量明显升高(P＜0.01)，给予红景天苷50mg·kg~(-1)·d-1治疗21日后，大鼠血清及海马MDA含量较AD模型组明显降低(P＜0.01)，但未回到正常水平。给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠血清及海马MDA含量也较AD模型组明显降低，差异达显著水平(P＜0.05)，但降低幅度不如红景天苷组。(4)与假手术组相比，AD模型组大鼠海马AchE活性明显升高(P＜0.01)，给予石杉碱甲0.05mg·kg~(-1)·d-1治疗21日后，大鼠海马组织AchE活性较AD模型组明显降低(P＜0.01)，但未回到正常水平。给予红景天苷50mg·kg~(-1)·d-1治疗21日后，大鼠海马组织AchE活性也较AD模型组明显降低(P＜0.05)，但其降低幅度小于石杉碱甲组，只有石杉碱甲组的约50%。
结论：红景天苷可能通过抑制Aβ1～40诱导的AD大鼠海马组织总ROS生成、提高血清及海马SOD活性、减少血清及海马MDA含量，从局部和整体提高了AD大鼠的抗氧化能力，减轻了神经组织氧化应激损伤。红景天苷与石杉碱甲在抗氧化损伤及抑制AchE活性能力方面各自具有不同的机制和优势。
3红景天苷对Aβ1～40所致AD模型大鼠海马NADPH氧化酶-ROS通路的影响
目的：NADPH氧化酶是细胞内ROS的主要来源。本实验通过观察NADPH氧化酶的表达与激活，对红景天苷抑制AD模型大鼠海马组织ROS产生的上游机制进行探讨。
方法：Aβ1～40海马内注射制备AD大鼠模型,术后给予红景天苷(50mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，用Westernblot检测大鼠海马组织中gp91phox及p47phox蛋白表达，用RT-PCR技术检测大鼠海马gp91phox及p47phoxmRNA水平，用免疫沉淀结合Westernblot分析检测大鼠海马组织中P47phox蛋白磷酸化水平。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)Western Bolt结果显示，Aβ1～40可诱导AD模型大鼠海马组织gp9lphox及p47phox蛋白表达，使其明显升高。AD模型组两种蛋白的含量分别是假手术组的2.39倍及2.71倍(P＜0.01)。而给予红景天苷治疗后，大鼠海马组织gp9lphox及p47phox蛋白表达较AD模型组分别降低了32.6%及46.1%(P＜0.01)。(2)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织gp9lphox及p47phoxmRNA表达明显升高，分别为假手术组mRNA水平的1.99倍及2.12倍(P＜0.01)。而给予红景天苷治疗，能够明显抑制Aβ1～40的这种诱导效应。红景天苷组较AD模型组分别降低了36.5%及26.8%(P＜0.01)。(3)IP-Western Bolt结果显示，假手术组p47phox的磷酸化水平相对较低，给予Aβ1～40刺激的AD模型组p47phox磷酸化水平较高，为假手术组的5.13倍，红景天苷治疗组p47phox的磷酸化水平明显降低，较AD模型组下降了44.5%，但未回到正常水平。
结论：红景天苷能够抑制Aβphox1～40诱导的AD海马组织gp9l与p47phoxmRNA转录、蛋白表达及亚基活化。说明红景天苷抑制NADPH氧化酶产生ROS，可能是通过抑制其亚基表达和抑制其亚基激活，两者协同作用的结果。红景天苷通过对NADPH氧化酶-ROS通路的抑制，减轻了Aβ诱导的AD脑内氧化应激反应。
4红景天苷对Aβ1～40所致AD模型大鼠海马ROS-NF-κB信号通路的影响
目的：ROS的生成不但能够直接攻击神经元细胞，造成神经损伤，还可作为细胞内重要的信使，介导与活化多种信号转导通路，造成炎症反应，间接导致神经组织和细胞的损伤。NF-κB可由ROS激活，并促进多种炎性因子的转录。由Aβ-ROS-NF-κB再到下游炎性基因这条信号通路，在AD的炎性进程中具有重要的意义。本实验通过观察红景天苷对Aβ1～40所致AD模型大鼠海马ROS-NF-κB信号通路的影响，进一步揭示红景天苷抑制脑内炎性损伤的机制。
方法：Aβ1～40海马内注射制备AD大鼠模型,术后给予红景天苷(50mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，用免疫组化及Westernblot检测大鼠海马组织中NF-κB、IκBα蛋白表达，用RT-PCR技术检测大鼠海马NF-κB及IκBα mRNA水平，用Westernblot分析磷酸化NF-κB蛋白水平，用免疫沉淀结合Westernblot分析检测大鼠海马组织中IκBα蛋白磷酸化水平。数据用xˉ±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)免疫组化结果显示：假手术组大鼠海马组织内NF-κB染色阳性细胞少，着色浅。AD模型组海马组织细胞内NF-κB染色阳性细胞数明显增多，内含大量棕黄色阳性颗粒。红景天苷组阳性细胞数较AD模型组明显减少，着色变浅。Western Bolt结果亦显示，给予Aβ1～40海马注射后，AD模型组大鼠海马组织NF-κB蛋白表达较假手术组显著升高，为假手术组的2.43倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织NF-κB蛋白表达较AD模型组降低了32.9%，差异显著(P＜0.01)。(2)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织NF-κB mRNA表达明显升高，为假手术组的2.07倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织NF-κB mRNA表达较AD模型组降低了35.9%(P＜0.01)。(3)免疫组化对NF-κB蛋白的定位显示：假手术组大鼠海马组织仅有少数细胞胞浆内有NF-κB染色的棕黄色阳性颗粒，且着色浅，胞核内几乎未见染色。AD模型组海马细胞的胞浆与胞核中均可见大量棕黄色阳性颗粒分布，较假手术组明显增多，红景天苷组海马细胞的胞核中NF-κB阳性颗粒较AD模型组明显减少。IP-Western Bolt结果显示：假手术组大鼠海马组织中NF-κB的磷酸化水平相对较低，给予Aβ1～40的模型组大鼠海马组织中NF-κB磷酸化水平较高，为假手术组的4.91倍(P＜0.01)，红景天苷治疗组大鼠海马组织中NF-κB磷酸化水平明显降低，较AD模型组下降了53.5%(P＜0.01)，但未回到正常水平。(4)免疫组化结果显示：AD模型组大鼠海马组织细胞内IκBα阳性染色细胞数较假手术组明显减少，而红景天苷组IκBα阳性染色细胞数较AD模型组明显增多。Western blot结果亦显示给予Aβ1～40海马注射后，AD模型组大鼠海马组织内IκBα水平较假手术组明显下降，降幅达58.7%(P＜0.01)，给予红景天苷治疗后，大鼠海马组织IκBα水平明显回升，较AD模型组上升了99.2%(P＜0.01)。(5)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织IκBα mRNA表达明显降低，降幅达62.7%(P＜0.01)。给予红景天苷治疗后，大鼠海马IκBα mRNA表达较AD模型组升高了92.2%(P＜0.01)。(6)IP-Western Bolt结果显示，假手术组IκBα的磷酸化水平相对较低，给予Aβ1～40的模型组大鼠海马组织中IκBα磷酸化水平较高，为假手术组的2.98倍，红景天苷治疗组大鼠海马IκBα的磷酸化水平明显降低，较AD模型组下降了33.4%。
结论：一方面红景天苷通过抑制Aβ1～40诱导的NF-κB蛋白表达起到抑制ROS-NF-κB通路的作用，另一方面红景天苷通过抑制IκBα的磷酸化降解、增强IκBα的表达，起到抑制NF-κB激活进而抑制ROS-NF-κB通路的作用。这对于抑制Aβ介导的脑内炎症反应具有重要的意义。
5红景天苷对Aβ1～40所致AD模型大鼠海马iNOS及RAGE表达的影响
目的：iNOS及RAGE受到NF-κB的诱导表达后，不但自身能直接介导Aβ诱导的多种神经毒性作用，还能反过来再次激活NF-κB，放大炎性效应，造成恶性循环。本实验通过对iNOS及RAGE表达的观察，进一步探讨红景天苷对Aβ1～40所致AD模型大鼠脑内氧化应激及炎症反应的综合干预作用。
方法：Aβ1～40海马内注射制备AD大鼠模型,术后给予红景天苷(50mg·kg~(-1))灌胃治疗，每日1次共21日。建模成功后，用免疫组化及Westernblot检测大鼠海马组织中iNOS及RAGE蛋白表达，用RT-PCR技术检测大鼠海马iNOS及RAGE mRNA水平。数据用ˉx±s表示，用SPSS统计分析软件进行统计学分析，用ANOVA及LSD进行组间比较及两两比较，P<0.05为有显著性差异。
结果：(1)免疫组化结果显示：假手术组大鼠海马组织内iNOS染色阳性细胞少，着色浅。AD模型组海马组织细胞内iNOS染色阳性细胞数明显增多，内含大量棕黄色阳性颗粒。红景天苷组阳性细胞数较AD模型组明显减少，着色变浅。(2)Western Bolt结果亦显示，给予Aβ1～40海马注射后，AD模型大鼠海马组织iNOS蛋白表达较假手术组显著升高，为假手术组的3.72倍。(P＜0.01)。给予红景天苷治疗后，大鼠海马组织iNOS蛋白表达较模型组降低了47.4%(P＜0.01)。(3)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织内iNOS mRNA表达明显升高，为假手术组的2.08倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织iNOS mRNA表达较模型组降低了37.0%(P＜0.01)。(4)免疫组化结果显示：假手术组大鼠海马组织细胞内，几乎没有RAGE染色的棕黄色阳性颗粒。AD模型组海马细胞内RAGE染色阳性细胞数明显增多，红景天苷组RAGE染色阳性细胞数较AD模型组明显减少。(5)Western Bolt结果亦显示，给予Aβ1～40海马注射后，AD模型大鼠海马组织RAGE蛋白表达较假手术组显著升高，为假手术组的1.86倍。(P＜0.01)。给予红景天苷治疗后，大鼠海马组织RAGE蛋白表达较模型组降低了31.4%(P＜0.01)。(6)RT-PCR结果显示，与假手术组相比，AD模型组大鼠海马组织RAGE mRNA表达明显升高。为假手术组的1.65倍(P＜0.01)。给予红景天苷治疗后，大鼠海马组织RAGEmRNA表达较模型组降低了23.8%(P＜0.01)。
结论：红景天苷通过抑制Aβ1～40诱导的大鼠海马组织内NF-κB-iNOS、NF-κB-RAGE信号通路及其反馈激活，遏制了氧化应激与炎性损伤相互作用、相互促进的恶性循环，对神经组织起到综合保护作用。
Alzheimer’s disease (AD) is a chronic progressive neurodegenerativedisorder. It is characterised clinically by progressive loss of memory,cognitive dysfunction and personality changes as the three primary groups ofsymptoms. Pathogenesis of AD is complex and not fully understood yet.People proposed various hypotheses with respect to etiology of AD，such asthe amyloid hypothesis, the tau proteins hypothesis, the cholinergic hypothesis,the dysmetabolism hypothesis, the free radicals and apoptosis hypothesis, theexcitatory amino acids hypothesis, the genic mutation hypothesis, et al.However, none of them can fully explain the pathogenesis of AD. With thedevelopment of research, people have come to realized that the oxidativestress, inflammation which are widespread reactions in the body haveinseparable connection with AD.
Plenty of evidence shows that abnormal metabolism of β-amyloid (Aβ)peptides and accumulation of excessive Aβ plays a critical role in progress ofAD. Abnormal deposition of Aβ can activate microglia secreteproinflammatory molecules and cellular factors, induce nicotinamide adeninedinucleotide phosphate oxidase (NADPH oxidase) to generate reactive oxygenspecies (ROS), activate nuclear factor-κB (NF-κB), induce the expression oftumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS).These reactions exert direct or indirect injuries of nervous system. Increasingevidence demonstrates that Aβ caused a series of neurotoxic effect whichcause neuron disfunction, death and further lead to dementia. Chronicinflammation in the brain and oxidative stress played significant roles in thiscourse. Anti-inflammatory and anti-oxidative therapy has become one of themost important strategies for the prevention and treatment of AD.
Plateau rhodiola is a perennial plant of Rhodiola family. It was a traditional famous Tibetan medicine. Researches show that rhodiola havespecial effects in preventing oxidative damage, scavenging free radicals,improving cell metabolism and enhancing cell vitality. Growing attention hasbeen received on it’s benefits of enhancing the brain function and improvingmemory, in the past few years. Animal experiments also showed that rhodiolamay have good prospects in the treatment of dementia and related fields.However, salidroside as the main effective component of rhodiola, its effectand mechanism on cognitive deficit of Alzheimer’s disease is still not clearand need systematic and profound researches.
The rat received intrahippocampal injection of Aβ is a mature model forAD. This model is closer to the real pathological processes of AD than othermodels, because of its good simulation of Aβ deposition in the brain. Aim toexplore the potential effects of salidroside on cognitive impairment of AD andthe related molecular mechanism, this study established Aβ1～40induced ratsmodel of AD. Systematical investigations were first undertaken from theaspects of behavior changes, generation of metabolism products, enzymologychanges in activity, protein expression, transcriptional regulation and so on.
1The effects of salidroside on cognitive deficits of AD model rats.
Objective: To establish Aβ1～40induced rat models of AD and observethe effects of salidroside on cognitive deficits of these models.
Methods: Male SD rats were randomly divided into6groups: shamcontrol group, AD model group, salidroside in small, medium and large dose(25mg·kg~(-1),50mg·kg~(-1),75mg·kg~(-1)) groups and huperzine A group(0.05mg·kg~(-1)). Aβ1～40was injected into bilateral hippocampus to create AD model.Rats were administered by gavage with salidroside for3weeks to determinethe protective and therapeutic effects on treatment rats. Morris water mazetesting system was undertaken to observe the changes of learning and memoryabilities in rats. Data were presented as xˉ±s and analyzed with multi-variatetest of repetitive measure ANOVA using SPSS statistical program.Enumeration data were analyzed with Rank sum test. A level of P<0.05wasconsidered statistically significant.
Results:(1) The analysis of the place navigation trial showed that theescape latencies decreased from Day1to Day5in all groups. The AD modelrats displayed longer escape latencies than the rats of sham control group(P＜0.01). The animals that treated with salidroside displayed significantlylower escape latencies than those in AD model group (P＜0.01). But therewas no significant difference between salidroside(25mg·kg~(-1))-treated groupand AD model group at the day1,2and5(P＞0.05). The animals inhuperzine A group displayed significantly lower escape latencies than those inAD model group (P＜0.05). Representative navigation paths at day5oftraining demonstrated that spatial learning acquisition was impaired in theanimals of AD model group relative to animals of salidroside-treated groupand huperzine A group.(2) In the spatial probe trial, The AD model rats spentsignificantly less time in the quadrant where the platform was hidden thananimals in sham control group (P＜0.01). The number of crossings to theprevious location of the platform was decreased in AD model group relative toanimals in sham control group (P＜0.01). Animals treated with salidroside(25mg·kg~(-1)) spent more time in the target quadrant and showed moreplatform-passing times than animals in AD model group, but there was nosignificant difference between them (P＞0.05). Animals in salidroside (50mg·kg~(-1),75mg·kg~(-1)) groups and huperzine A group spent more time in thetarget quadrant and showed statistically more platform-passing times thananimals in AD model group (P＜0.01).
Conclusions: The behavioural data obtained in the Morris water mazetest demonstrate that salidroside is able to protect animals from the memoryimpairments induced by intrahippocampal injection of Aβ1～40.
2The effects of salidroside on anti-oxidative activities of AD modelrats.
Objective: To observe the effects of salidroside on the generation of totalROS, the superoxide dismutase (SOD) activity, the malondialdehyde (MDA)level and the acetylcholinesterase (AChE) activity in serum and hippocampusof AD model rats.
Methods: Male SD rats were randomly divided into4groups: sham control group, AD model group, salidroside (50mg·kg~(-1)) group and huperzineA group (0.05mg·kg~(-1)). Aβ1～40was injected into bilateral hippocampus tocreate AD model. Rats were administered by gavage with salidroside for3weeks. The generation of total ROS in hippocampus was determined by flowcytomertry technology, the superoxide dismutase (SOD) activity and themalondialdehyde (MDA) level in serum and hippocampus as well as theacetylcholinesterase (AChE) activity in serum were determined by separatebiochemical kit. Data were presented as xˉ±s and analyzed with ANOVA andLSD using SPSS statistical program. A level of P＜0.05was consideredstatistically significant.
Results:(1) The results showed animals received intrahippocampalinjection of Aβ1～40displayed a significantly enhancement of ROS productioncompared with the sham control group (P <0.01). The level of ROS wassignificantly inhibited after treated with salidroside or huperzine A incomparison with the AD model group (P <0.01, P <0.01). The inhibition ofROS by huperzine A was weaker than that by salidroside.(2) Animalsreceived intrahippocampal injection of Aβ1～40displayed a significantlydecrease of the SOD activity in serum and hippocampus compared with thesham control group (P <0.01). The SOD activity was significantly increasedafter treated with salidroside or huperzine A in comparison with the AD modelgroup (P <0.01, P <0.01). The increase of SOD activity by huperzine A wasweaker than that by salidroside.(3) Intrahippocampal injection of Aβ1～40induced significant increase of the MDA level in the serum and hippocampusof AD model group (P <0.01). On the other hand, we observed a significanttrend for decrease of the MDA level after salidroside or huperzine A treatmentin comparison with the AD model groups (P <0.01, P <0.05). The decrease ofthe MDA level by huperzine A was weaker than that by salidroside.(4) ADmodel group showed a significantly increase of the AChE activity inhippocampus compared with the sham control group (P <0.01). The AChEactivity was significantly inhibited after treated with salidroside or huperzineA in comparison with the AD model group (P <0.05, P <0.01). The inhibition of AChE activity by salidroside was weaker than that by huperzine A.
Conclusions: Salidroside could significantly decrease the generation oftotal ROS in hippocampus, increase the SOD activity in serum andhippocampus, decrease the malondialdehyde (MDA) level in serum andhippocampus and inhibit the AChE activity in hippocampus of AD model rats.These effects enhanced the anti-oxidative activities and prevented the neuronaldamage from oxidative stress. There are different mechanisms and advantagesbetween salidroside and huperzine A on the effects of preventing oxidativedamage and suppressing AchE activity.
3The effects of salidroside on NADPH oxidase-ROS signalpathway in hippocampus of AD model rats.
Objective: NADPH oxidase is the main source of ROS in cells. In thepresent study, the expression and activation of NADPH oxidase inhippocampus of AD model rats were observed in order to elucidate the signalmechanism of salidroside on the suppressing generation of ROS.
Methods: Male SD rats were randomly divided into3groups: shamcontrol group, AD model group, salidroside (50mg·kg~(-1)) group. Aβ1～40wasinjected into bilateral hippocampus to create AD model. Rats wereadministered by gavage with salidroside for3weeks. The expression level ofgp91phoxand p47phoxprotein in hippocampus of AD model rats weredetermined by Westernblot. The expression level of gp91phoxand p47phoxmRNA were assayed by means of RT-PCR. The phosphorylation level ofp47phoxprotein was detected by immuno precipitation analysis. Data werepresented as xˉ±s and analyzed with ANOVA and LSD using SPSS statisticalprogram. A level of P＜0.05was considered statistically significant.
Results:(1) Western blot analysis showed that the expression level ofgp91phoxand p47phoxprotein in hippocampus of AD model rats weresignificantly increased by2.39times and2.71times, compared with shamcontrol group (P＜0.01). After treated with salidroside the expression levelof gp91phoxand p47phoxprotein in hippocampus of salidroside group weresignificantly inhibited by32.6%and46.1%respectively, in comparison with the AD model group (P＜0.01).(2) RT-PCR analysis showed that theexpression level of gp91phoxand p47phoxmRNA in hippocampus of AD modelrats were significantly rosed by1.99times and2.12times, compared withsham control group (P＜0.01). After treated with salidroside the expressionlevel of gp91phoxand p47phoxmRNA in hippocampus of salidroside group weresignificantly reduced by36.5%and26.8%respectively, in comparison withthe AD model group (P＜0.01).(3) IP-Western Bolt analysis showed that thephosphorylation level of p47phoxprotein in hippocampus of AD model ratswere significantly increased by5.13times, compared with sham control group(P＜0.01). After treated with salidroside the phosphorylation level of p47phoxprotein in hippocampus of salidroside group were significantly inhibited by44.5%respectively, in comparison with the AD model group (P＜0.01).
Conclusions: Salidroside could significantly decrease the genetranscription and protein expression as well as the subunit activation ofNADPH oxidase. The findings indicate that both the effects of suppressingsubunits expression and inhabiting subunit activation on NADPH oxidase,decreased the level of ROS in hippocampus, further reduced the oxidativedamage.
4The effects of salidroside on ROS-NF-κB signal pathway inhippocampus of AD model rats.
Objective: It has been demonstrated that activated microglia produceROS, which may induce or exacerbate neurotoxicity by causing oxidativestress to neurons. Studies also showed that ROS production was attributable tothe activation of NF-κB and consequent pro-inflammatory cytokines.Aβ-ROS-NF-κB signal pathway has been shown to play an important role inchronic inflammation during the onset and progression of AD. In the presentstudy, the activation of ROS-NF-κB signal pathway in hippocampus of ADmodel rats was observed in order to elucidate the signal mechanism ofsalidroside on the attenuation of inflammatory damage in the brain.
Methods: Male SD rats were randomly divided into3groups: shamcontrol group, AD model group, salidroside (50mg·kg~(-1)) group. Aβ1～40was injected into bilateral hippocampus to create AD model. Rats wereadministered by gavage with salidroside for3weeks. The expression level ofNF-κB and IκBα protein in hippocampus of AD model rats were determinedby Westernblot and Immunohistochemical analysis. The expression level ofNF-κB and IκBα mRNA were assayed by means of RT-PCR. Thephosphorylation level of NF-κB protein was detected by Westernblot. Thephosphorylation level of IκBα protein was detected by immuno precipitationanalysis. Data were presented asˉx±s and analyzed with ANOVA and LSDusing SPSS statistical program. A level of P＜0.05was consideredstatistically significant.
Results:(1) Western blot analysis showed that the expression level ofNF-κB protein in hippocampus of AD model rats were significantly increasedby2.43times, compared with sham control group (P＜0.01). After treatedwith salidroside the expression level of NF-κB protein in hippocampus ofsalidroside group were significantly inhibited by32.9%respectively, incomparison with the AD model group (P＜0.01). Immunohistochemicalanalysis showed the same trend as shown in Western blot. The NF-κB positivecells were increased in AD Model group and decreased in salidroside group.(2) RT-PCR analysis showed that the expression level of NF-κB mRNA inhippocampus of AD model rats were significantly rosed by2.07timescompared with sham control group (P＜0.01). After treated with salidrosidethe expression level of NF-κB mRNA in hippocampus of salidroside groupwere significantly reduced by35.9%respectively, in comparison with the ADmodel group (P＜0.01).(3) Western Bolt analysis showed that thephosphorylation level of NF-κB protein in hippocampus of AD model ratswere significantly increased by4.91times, compared with sham control group(P＜0.01). After treated with salidroside the phosphorylation level of NF-κBprotein in hippocampus of salidroside group were significantly inhibited by53.5%respectively, in comparison with the AD model group (P＜0.01).(4)Western blot analysis showed that the expression level of IκBα protein inhippocampus of AD model rats were significantly decreased by58.7%, compared with sham control group (P＜0.01). After treated with salidrosidethe expression level of IκBα protein in hippocampus of salidroside group weresignificantly rosed by99.2%respectively, in comparison with the AD modelgroup (P＜0.01). Immunohistochemical analysis showed the same trend asshown in Western blot. The IκBα positive cells were decreased in AD Modelgroup and rosed in salidroside group.(5) RT-PCR analysis showed that theexpression level of IκBα mRNA in hippocampus of AD model rats weresignificantly reduced by62.7%compared with sham control group (P＜0.01).After treated with salidroside the expression level of IκBα mRNA inhippocampus of salidroside group were significantly increased by92.2%respectively, in comparison with the AD model group (P＜0.01).(6)IP-Western Bolt analysis showed that the phosphorylation level of IκBαprotein in hippocampus of AD model rats were significantly increased by2.98times, compared with sham control group (P＜0.01). After treated withsalidroside the phosphorylation level of IκBα protein in hippocampus ofsalidroside group were significantly inhibited by33.4%respectively, incomparison with the AD model group (P＜0.01).
Conclusions: On the one hand salidroside could inhibit the ROS-NF-κBsignal pathway by reducing the NF-κB protein expression, on the other handsalidroside could inhibit the ROS-NF-κB signal pathway by reducing thephosphorylation level of IκBα protein and enhancing IκBα protein expression,both of which can inhibit the NF-κB activation. These effects have greatsignificance for attenuating Aβ-mediated inflammation in the brain.
5The effects of salidroside on iNOS and RAGE expression inhippocampus of AD model rats.
Objective: Excessive expression of iNOS and RAGE can be induced byNF-κB. These productions can not only mediate the neurotoxicity of Aβderectly by themselves, but also activate NF-κB again, which will amplify theinflammatory effects and resulted in vicious circles. In the present study, theexpression of iNOS and RAGE in hippocampus of AD model rats wereobserved in order to further elucidate the comprehensive intervention of salidroside on the oxidative stress and inflammation in the brain.
Methods: Male SD rats were randomly divided into3groups: shamcontrol group, AD model group, salidroside (50mg·kg~(-1)) group. Aβ1～40wasinjected into bilateral hippocampus to create AD model. Rats wereadministered by gavage with salidroside for3weeks. The expression level ofiNOS and RAGE protein in hippocampus of AD model rats were determinedby Westernblot and Immunohistochemical analysis. The expression level ofiNOS and RAGE mRNA were assayed by means of RT-PCR. Data werepresented as xˉ±s and analyzed with ANOVA and LSD using SPSS statisticalprogram. A level of P＜0.05was considered statistically significant.
Results:(1) Western blot analysis showed that both the expression levelof iNOS and RAGE protein in hippocampus of AD model rats weresignificantly increased by3.72times and1.86times, compared with shamcontrol group (P＜0.01). After treated with salidroside the expression levelof iNOS and RAGE protein in hippocampus of salidroside group weresignificantly inhibited by47.4%and31.4%respectively, in comparison withthe AD model group (P＜0.01). Immunohistochemical analysis showed thesame trend as shown in Western blot. Both of the iNOS and RAGE positivecells were increased in AD Model group and decreased in salidroside group.(2) RT-PCR analysis showed that the expression level of iNOS and RAGEmRNA in hippocampus of AD model rats were significantly rosed by2.08times and1.65times compared with sham control group (P＜0.01). Aftertreated with salidroside the expression level of iNOS and RAGE mRNA inhippocampus of salidroside group were significantly reduced by37.0%and23.8%respectively, in comparison with the AD model group (P＜0.01).
Conclusions: Salidroside could inhibit the activation of NF-κB-iNOSand NF-κB-RAGE signal pathways and their feedback loop in hippocampus ofAD model rats. All of these effects might suppress the interaction and thevicious cycle from mutual promotion between oxidative stress andinflammatory damage, that would give a comprehensive protection fornervous tissue.
引文
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