| 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. |
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