摘要
人类社会目前正进入老龄化。老龄化社会是指一个国家60岁以上人口达总数10%或65岁以上人口达7%。我国第6次人口普查结果显示：我国总人口13.39亿，其中60岁以上人口占13.26%，65岁以上人口占8.87%。因此我国已步入老龄化社会。正常生理调节下的老龄化往往可以导致不同程度的学习记忆及认知功能减退。各种原因，如糖尿病、高血压、高脂血症、脑梗死、脑出血、脑白质疏松及慢性脑缺氧等因素均可导致各种程度的认知功能障碍(Cognitive Functional Impairments)，甚至可以发生痴呆等神经退行性病变。随着老年人口增加，因年龄增长而出现的认知功能障碍已成为影响老年人健康和生活质量的重要问题。朱晓琼采用随机整群抽样的方法对乌鲁木齐3个社区，年龄≥60岁的1511位老年人进行现况调查，结果表明认知障碍者占9.79%，且与受教育程度有关。关绍晨抽样调查北京地区60岁及以上老年人1750人，其中认知障碍203例，患病率为11.6%；年龄大于75岁者的患病率高达15.7%。以临床病人为基础的研究中，认知功能障碍进展为老年性痴呆的比率为每年10-15%，而以人口构成为基础的研究中转化的比率相对较低，为每年5-10%，其比率随年龄增加及低受教育水平而增加，这种差别可能与人群的特征、随访年限以及认知的定义不同有关。
老年性痴呆(Alzheimer's disease，AD)是一种中枢神经系统退行性疾病，其主要神经病理改变为神经元变性、突触可塑性改变引起的脑萎缩、细胞外β-淀粉样蛋白(β-amyloid，Aβ)沉积形成的老年斑(senile plaque，SP)和细胞内蛋白异常磷酸化导致的神经纤维缠结(neurofibrillary tangle，NFT)，这些病理改变主要集中于顶叶、颞叶、额叶联合区和与学习记忆密切相关的海马。近年来大量的研究表明糖尿病认知功能障碍与AD密切相关，二者均可出现认知功能障碍的临床表现，如记忆障碍、失语、失认、失用及视空间障碍等，还可伴随焦虑、抑郁、激越、冲动等情感行为障碍。AD病理变化亦可出现于糖尿病认知功能障碍的患者及动物模型中。近年研究证明糖尿病是AD发病的独立危险因素，有学者更将AD定义为3型糖尿病，并认为导致糖尿病认知功能障碍的主要原因如脑葡萄糖利用障碍及中枢胰岛素抵抗亦存在于AD患者。
无论是糖尿病认知功能障碍，还是AD早期表现的认知功能障碍，目前尚无确切有效的药物治疗，仅从改善症状入手，采用的改善认知功能障碍的药物主要包括胆碱能药、谷氨酸受体调控剂、抗氧化剂、神经营养因子及受体生成药物、激素类及钙拮抗剂等几大类，但由于不良反应的影响，患者往往无法坚持长期应用，从而限制了这些药物的临床应用。中药由于其源自天然植物，具有资源丰富，毒副作用小，利于长期应用等特点而被科研工作者关注。2009年Brian H.研究组对2007年2月之前中药改善认知功能的中英文数据进行荟萃分析，结果表明中药(天然药物的主要范畴)对改善认知和学习记忆障碍，治疗和预防早期痴呆(包括血管性痴呆和老年性痴呆)均有良好效果，且无严重不良反应的报告。因此，研究和开发中药改善认知功能具有广阔的应用前景和重要的临床意义。
组分中药是以中医学理论为基础，以现代科学思想为指导原则，以临床有效的名优中药为基础，遵循传统方剂的配伍原则，在基本搞清方剂药效物质和作用机理的基础上，以组效关系为基础，优化设计出针对临床适应病证有效的中药处方。它是一种新的中药研究理论体系，以“标准组分、组效关系、配伍配比优化设计”为技术特征，配伍理论遵循中医学中方剂学的理论原则，适应现代化制造业的工艺技术和质量标准要求，能够达到安全有效、质量可控，适于规模化生产，并且作用成分更为明确，机理更清楚，临床适应病症更确切，具有更强的针对性。
本研究的组分中药金智达是导师战丽彬教授领导的课题组根据组分中药原理研发的新药，分别将人参、远志的提取物人参茎叶皂苷及远志皂苷，与近年来研究较多的具有明确改善认知及学习记忆作用的绿茶中提取的有效成分茶氨酸和茶多酚进行合理组方，使其具有益气安神益智的功效。本课题组既往曾应用滋补脾阴方药对老年性痴呆及糖尿病认知功能障碍等多种动物模型、体外细胞模型及临床患者进行干预，取得确切疗效；并通过蛋白质组学、分子生物学手段对滋补脾阴方发挥神经保护、改善认知障碍的作用机制进行系列研究，发现内质网应激在AD及糖尿病认知功能障碍发病中均有重要作用。本研究应用组分中药金智达对高脂加小剂量胰岛素诱导的糖尿病大鼠模型及东莨菪碱诱导的学习记忆障碍小鼠模型动物模型进行干预，考察糖尿病认知功能障碍及AD相关的认知功能障碍的改善作用；并通过内质网应激介导的胰岛素信号转导初步探讨糖尿病相关认知功能障碍的发病机制及组分中药金智达对此信号转导通路的影响。
目的：1.应用高脂加小剂量STZ诱导的2型糖尿病大鼠模型探讨组分中药金智达对糖尿病认知功能障碍的影响；2.应用东莨菪碱诱导的学习记忆障碍小鼠模型，探讨组分中药金智达对老年性痴呆认知功能的影响；3.观察内质网应激诱导的胰岛素信号转导通路在糖尿病大鼠海马的变化，初步探讨糖尿病认知功能障碍发病的可能机制及组分中药金智达改善糖尿病认知功能障碍的可能作用靶点。
方法：1. SPF级健康成年雄性SD大鼠分为正常对照组、模型对照组、低、中、高剂量组分中药金智达组5组，每组5只。以高脂饲料喂养4周，后给予30mg/kg剂量一次性腹腔注射1%的链脲佐菌素(Streptozocin, STZ)溶液建立2型糖尿病模型。在STZ注射后的第4天检测空腹血清胰岛素水平(Fasting Serum Insulin,FSI)，第8天进行口服葡萄糖耐量实验(Oral Glucose Tolerance Test,OGTT)，第12天行胰岛素耐量实验(Insulin Tolerance Test,ITT)。糖尿病模型建立期间观察各组大鼠的一般状况。第8周开始组分中药金智达治疗，对糖尿病各组分别给予低、中、高剂量组分中药金智达干预，共5周。在第12周进行跳台实验(Step down test)和Morris水迷宫实验(Morris water maze test)，比较各组大鼠学习记忆能力的改变。2.清洁级昆明小鼠40只，随机分为正常对照组、模型对照组、低、中、高剂量组分中药金智达组5组，每组8只。各组适应性喂养3天后，分别给予低、中、高剂量组分中药金智达干预，正常对照组和模型对照组分别给予等体积生理盐水灌胃，连续给药15天。第7天始，各组动物给药后30min，行为学测试前10分钟以2mg/kg的东莨菪碱腹腔注射模拟学习记忆障碍模型，模型建立后相继进行避暗、跳台和水迷宫实验，比较各组东莨菪碱所致学习记忆障碍模型小鼠学习记忆能力的改变。3.通过Western blot方法观察糖尿病大鼠海马内质网应激标志(eIF2α，IRE-1α，PERK，GRP78)分子和胰岛素信号转导通路标志分子(JNK，IRS-1，Akt)的蛋白磷酸化变化。
结果：1.高脂喂养大鼠第2周开始出现体重增加，喂养至第4周时，与普通饲料喂养大鼠相比，高脂喂养大鼠体重增加明显，差异具有统计学意义(P<0.05)。高脂喂养阶段，大鼠的一般状况良好，各组间饮食量、饮水量和肛温无统计学差异；STZ注射后糖尿病组大鼠随机血糖明显高于正常对照组大鼠，差异具有统计学意义(P<0.01)。OGTT结果提示糖尿病组大鼠出现明显糖耐量异常； ITT实验中糖尿病组大鼠血糖下降速率比正常对照组大鼠血糖下降速率减慢，验证糖尿病组大鼠存在胰岛素抵抗。空腹血清胰岛素水平(FSI)糖尿病组明显高于正常对照组(P<0.05)，验证糖尿病大鼠存在高胰岛素血症。行为学结果显示：模型对照组学习记忆成绩较正常对照组下降明显(P<0.05)，高剂量组分中药金智达组可以明显改善糖尿病大鼠的学习记忆成绩，与模型对照组比较具有统计学意义(P<0.05)。2.东莨菪碱诱导的学习记忆障碍模型组小鼠避暗潜伏期缩短，错误次数增加，与正常对照组比较有统计学意义(P<0.01)，提示成功构建了学习记忆障碍的小鼠模型；低、中、高剂量组分中药金智达组与模型组比较，避暗潜伏期延长(P<0.01)，错误次数减少(P<0.05)；药物干预各组避暗潜伏期与正常对照组的成绩比较，差异有统计学意义(P<0.05)，错误次数的差异无统计学意义(P>0.05)；跳台实验中，模型组与正常对照组及低、中、高剂量组分中药金智达组比较潜伏期缩短(P<0.01)，错误次数增加(P<0.05)；经组分中药金智达治疗后小鼠的学习记忆能力明显提高，虽然成绩与正常对照组比较潜伏期仍短，错误次数相对偏多，但此差异无统计学意义(P>0.05)；水迷宫实验中，模型组潜伏期与正常对照组比较明显延长(P<0.05)，低、中、高剂量组分中药金智达组潜伏期与模型组比较明显缩短，差异具有统计学意义(P<0.05)；虽然组分中药金智达干预后潜伏期没有达到正常对照组水平，但二者差异无统计学意义(P>0.05)；分析水迷宫实验中的游泳距离，得到与潜伏期成绩一致的结果。3.糖尿病大鼠存在内质网应激，并通过启动上游分子PERK、IRE-1α、eIF-2α磷酸化激活内质网应激，使分子伴侣GRP78代偿性增加；内质网应激启动后，激活其下游JNK磷酸化；JNK磷酸化进而导致胰岛素信号转导通路上IRS-1丝氨酸307位点磷酸化，引起胰岛素信号转导障碍，使胰岛素信号转导通路的重要下游分子Akt磷酸化表达减少；而组分中药金智达可以通过干预上述信号转导，发挥改善认知功能的作用，尤其是高剂量组分中药金智达组效果显著，与模型对照组比较差异具有统计学意义(P<0.05)。
结论：1.应用高脂饮食配合小剂量STZ注射可以成功构建2型糖尿病大鼠模型，在2型糖尿病大鼠模型构建12周之后经行为学验证，糖尿病大鼠出现学习记忆能力下降，提示糖尿病大鼠存在认知功能障碍；组分中药金智达有改善糖尿病大鼠学习记忆能力的作用，其中高剂量组效果尤著。2.氢溴酸东莨菪碱可以成功构建学习记忆障碍模型，组分中药金智达有改善氢溴酸东莨菪碱诱导的学习记忆障碍模型小鼠学习记忆能力的作用。3.糖尿病认知功能障碍大鼠海马存在内质网应激，通过组分中药金智达干预可以减轻内质网应激，高剂量组分中药金智达组更为明显；糖尿病认知功能障碍大鼠海马出现胰岛素信号转导障碍，并且与内质网应激激活导致的JNK活化密切相关；组分中药金智达可以通过抑制JNK活化，抑制IRS-1丝氨酸磷酸化，从而改善胰岛素信号转导障碍，高剂量组作用效果显著。组分中药金智达通过抑制内质网应激，减轻胰岛素抵抗，进而恢复胰岛素信号转导的正常功能，从而发挥改善认知功能的作用，这可能是其治疗糖尿病认知功能障碍的机制之一。
Aging is coming to the human society. The aging society means a nationalpopulation over the age of60up to10%or over the age of65up to7%. In the sixthcensus the results show that: China's total population was1.339billion, whichaccounted for13.26%of people aged over60and8.87%of the people aged over65.Therefore, China has entered the aging society. Under normal physiological regulation,aging can lead to different levels of learning and memory and cognitive dysfunction. Avariety of reasons, such as diabetes, hypertension, hyperlipidemia, cerebral infarction,cerebral hemorrhage, Leukoaraiosis and chronic cerebral hypoxia and so on, may alsolead to various degrees of cognitive impairment, even dementia and otherneurodegenerative diseases. With the elderly population increasing, ageing andcognitive dysfunction has become the important issues affecting olderr persons healthand quality of life. Zhu Xiaoqiong made the current situation survey using randomcluster sampling method in three communities of Urumqi, aged over60years of1511elderly people, the cognitive impairment accounted for9.79%, relating with the level ofeducation. Guan Shao-Chen sample survey of Beijing in60years of age and older1,750,including203cases of cognitive impairment, the prevalence was11.6%; prevalence ofover75years of age up to15.7%. Clinical patient-based research, the ratio of cognitiveimpairment progressed to dementia each year10-15%of the population. The rate was5-10%basing on population and incresed with age and low educational level. Thisdifference may be related to the characteristics of the population follow-up period, andcognitive amount defined. cognitive impairment is the pristine clinical appearance inAlzheimer’s disease(AD)AD is a severe neurodegenerative disorder which hasapparente pathological characteristics: neuronal degeneration， synaptic plasticityinducing encephalatrophy， β-amyloid deposition forming senile plaque and tau abnormal phosphorylation forming neurofibrillary tangles. These pathological changesmainly appeared parietal lobe, temporal lobe, frontal lobe association area andhippocampus. Many researches had shown that there were closed orrelation betweendiabetic association cognitive impairment. In diabetic patients and animals ADpathological changes were found. Meanwhile, diabetic mellitus was been certificated arisk factor of AD and AD was been thought as “type3diabeitc mellitus”. Bain glucoseunutilization and insulin resistance also consisted in AD. While the incidence ofcognitive impairment with age had been impacted on the health and life quality and ledto patients disability, which included not only the performance of memory disorders,aphasia, amnesia, apraxia or visual-spatial disorders, but also accompanied by anxiety,depression, agitation, emotional behavioral disorders and other impulsive, emotionaland behavioral problems. All of these were also the important reasons for patientsmutilation and meanwhile they brought a heavy burden for society and family.
Nowadays the common drug treatments for improving learning and cognitiveinclude cholinergic drugs, glutamate receptor modulators, antioxidants, neurotrophicfactors and their receptors generated by drugs, hormones and other types drugs.However, with the side effects and adverse effects, patients are unable to long-term use.Thus these treatments were limited to clinical application. Natural plants rich resources,minor side effects and feature of long-term application, so the scientific researchworkers have shown solicitude for them. In2009, Brian H. made a systematic reviewaimed to assess the effectiveness and safety of herbal medicines (HM, the majority ofnatural plants) for treating and preventing the early dementia (including the vasculardementia and Alzheimer’s disease), the databases in English and Chinese were searchedfrom their inceptions to February2007. The conclusions showed that Chinese herbalmedicine could improve cognitive and memory, treat and prevent cognitive functionimpairment. The effects were significant and no serious adverse reactions werereported. Therefore, the researches and developments of Multi component ChineseMedicine Jinzhida to improve cognitive function were very meaningful with the wideapplicability prospects and great significance.
Multi-component Chinese medicine is based on the traditional Chinese medicinetheory and could be guided by the complexity science thought. Multi-componentChinese medicine was made of clinical effective extracts from famous traditionalChinese medicine and recipes, which were the material of the clear active mechanismsand pharmaodynamic features. The researchers designed these Multi-component Chinese medicine according to the composition-activity relationship and clinicaladaptative diseases and selected the useful prescriptions of traditional Chinese medicine.Multi-component Chinese medicine theory is a new theory system, with the followingtechnical characteristics “the standard component, the composition-activity relationship,compatibility proportion optimization design”, which could be adapt to modernmanufacturing technology and quality standards, could achieve safe and effective,controllable quality, suitable for the large scale production. Meanwhile,Multi-component Chinese medicine theory abides by the principle of compatibility oftraditional Chinese Medicine. In a word, Multi-component Chinese medicine was clearfor active component, identified for mechanism, extract for clinical adaptative diseasesand had more powerful direction.
The Multi component Chinese Medicine Jinzhida (JZD) is a complex extractsdesigned according to the theory of Multi-component Chinese medicine by our researchteam. In this work, the Multi component Chinese Medicine Jinzhida was made of fourextracts which were theanine, tea polyphenols, ginsenosides and polygalic acids fromChinese herbs tea, ginseng and polygala respectively, all constituents were proved to beeffectivly nueroprotective medicine which could ameliorate cognitive decline inducedby Alzheimer disease with benefiting vital energy, calming the nerves and growing inintelligence effects.
Objective: To study the mechanism in Multi component Chinese MedicineJinzhida improved cognitive functions by different cognitive impaired animal models.To discuss the possible mechanism and drug targets in the insulin signal transductioninducing by endoplasmic reticulum stress in the diabetic encephalopathy rats model.
Methods:1. The healthy male Sprague–Dawleys (SD) rats were divided into fivegroups, which were a control group, a diabetic mellitus model group and three modeltreatment groups for low, middle, high different dose of Multi component ChineseMedicine Jinzhida, each group contained5rats. After4weeks high fat diet, the modelgroups’ rats were injected1%streptozotocin (STZ) solution to establish diabetesmodels, with the dose to30mg/kg. The fasting serum insulin levels (FSI), oral glucosetolerance test (OGTT) and insulin tolerance test (ITT) were dected respectively aftermodeling4,8,12days and the common condition were observed during modeling. After8weeks, rats were treated with the different dose of Multi component Chinese MedicineJinzhida for5weeks. In the12weeks, the behavioral abilities were dected by Stepdown test and Morris water maze, then the learning and memory changes were compared among the different groups.2. Kunming mice were divided into five groups,which were a control group, an Alzheimer’s disease model group and three modeltreatment groups for low, middle, high different dose of Multi component ChineseMedicine Jinzhida, each group contained8animals. After3days adaptive feeding, thedifferent doses of Multi component Chinese Medicine Jinzhida were treated for15days.From the7th day, the models were injected scopolamine solution to establish ADmodels before30minutes of the behavioral tests for step-though test, Step down testand Morris water maze, then compared learning and memory changes in differentgroups.3. Detected the Protein levels of endocytoplasmic reticulum stress(ERS)andinsulin signal transduction biological markers, such as phosphorylated protein kinaseRNA-like endoplasmic reticulum kinase (PERK), subunit of translation initiationfactor2α (eIF2α), inositol-requiring enzyme-1α(IRE-1α), Jun NH2-terminalkinases(JNK), insulin receptor substrate-1(IRS-1) phosphoserine-307and Akt bywestern blotting for the type2diabetic rats’ hippocampus.
Results:1. After2weeks high fat diet, the rats body weight began to increase, upto4weeks, the body weight increased more in the high fat diet group than in thecommon fat diet group(P<0.05). During the high fat diet, all rats were generally in goodcondition and there were no significantly difference in eating, drinking and rectaltemperature between two diets feeding. After STZ injection, the type2diabetic ratsshowed high blood-glucose levels and poor glucose and insulin tolerance comparedwith the control rats, it respectively showed the sugar tolerance abnormality, insulinresistant and hyperinsulinemia in diabetic model group. In the behavioral experiments,diabetes caused impairment in acquisition and retrieval processes of step-down test andspacal memory of Morris water maze test in the diabetic encephalopathy group(P<0.05).The Multi component Chinese Medicine Jinzhida improved the learning and memorydeficits, especially, in high-dose treated diabetic rats(P<0.05).2. The AD model miceshowed passive avoidance latency decreasing and number of errors increasing morethan the control group(P<0.01), it proved that we made the AD rouse modelsuccessfully. In the passive avoidance test, Multi component Chinese Medicine Jinzhidatreatment groups compared with model group, the passive avoidance latency wasprolonged(P<0.01) but the number of errors was no difference (P>0.05). In the stepdown test, the model group short incubation period, the number of errors increasedcompared with the normal control group and the Multi component Chinese MedicineJinzhida intervention each dose group, the difference were significantly (P<0.01). After the intervention the achievements in three model treatment groups significantlyincreased, though the results were not statistically significant compared with normalcontrol group (P>0.05). In water maze test, incubation period of each model groupwas significantly longer than the normal control group (P<0.05), the incubation periodin Multi component Chinese Medicine Jinzhida treatment groups had also beenstatistically shortened compared with the model group (P<0.05). The treatment did notmeet the normal incubation period after the intervention control level, but thisdifference was not statistically significant (P>0.05). Analysising the water Maze testswimming distance, the results were consistent with the conclusions of the incubationperiod.3. Type2diabetic rats with diabetic encephalopathy occurred endoplasmicreticulum stress, and following the UPR upstream molecules PERK, IRE-1α, eIF-2αphosphorylation activates expression. The molecular chaperone GRP78expressionincreased as compensatory, and then endoplasmic reticulum stress promoted aJNK-dependent serine phosphorylation of IRS-1, which in turn inhibited insulin signaltransduction. As a result, insulin resistance occurred and insulin signal transductionimpaired. The Multi component Chinese Medicine Jinzhida reduced ERS andimproved the insulin signal transduction and insulin resistance, especially the high-dosegroup, which was significantly different with diabetic encephalopathy group(P<0.05).
Conclusion:1.The Multi component Chinese Medicine Jinzhida improved thelearning and memory ability in type2diabetic rats, by increasing the step-down test andwater Maze performance, especially the high dose Multi component Chinese MedicineJinzhida group.2. The scopolamine coule induce the learning and memory dysfunctionfor the mechanism and drugs research of Alzheimer’s disease. The Multi componentChinese Medicine Jinzhida increased the passive avoidance, step-down and water mazetests performance in the scopolamine induced learning and memory dysfunction micemodel.3. The possible mechanism for Diabetes-Associated Cognitive Decline wasrelated with endoplasmic reticulum stress inducing the insulin signal transductiondysfunction in type2diabetic mellitus rats’ hippocampus. The Multi componentChinese Medicine Jinzhida could reduce ERS and improve insulin signal transductionand insulin resistance in type2diabetic rats’ hippocampus and as a result improved the cognitive function, especially the high dose Multi component Chinese MedicineJinzhida group.
引文
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