Druggability Research And The Effects And Potential Mechanism Of Kaixin Yizhi Granules Against Cognitive Impairment Of Rats

Cognitive impairment(CI) is a pathological phenomenon which processed from abnormal course of brain handle external information, and it according to the disorder in different acknowledge regions should be divided into learning, memory obstacles analyzes obstacles, the obstacles of judgment, attention obstacles, etc. Mild cognitive impairment(MCI) is a syndrome which is common in older people, and is a clinical state between normal aging and mild dementia, that mainly showed an obvious memory disorder or other mild cognitive dysfunction, but it does not affect the daily life. MCI is divided into oblivion type and non-oblivion type. The former is one of the early clinical symptoms of Alzheimer’s disease(AD), and nearly 15% of patients with MCI into AD in each year. MCI of non-oblivion type is one of the early clinical symptoms of vascular dementia(Va D), dementia in frontotemporal fasciculus, AD and other dementia. To pay attention to the diagnosis and treatment of MCI, it can be found early, intervened early, and provide the best time-window of therapy, to delay or prevent the occurrence and development of dementia.It is an important manifestation of MCI and AD that identify the cognitive decline. The fading, languor, and denaturation of brain are its base. On the pathogenesis of CI, there are cholinergic system theory, β-amyloid protein concatenation theory, chondriosome concatenation theory. ACH is an important neurotransmitter, which released by cholinergic neurons tip, and involved in signal transduction, and is closely related to the process of learning and memory. The effect of ACHE is to resolve ACH. However the effect of CHAT is to produce specificity enzyme of ACH. Research showed that, imitate cholinergic drugs could improve the learning and memory function, and anti-cholinergic drugs damage the function of learning and memory.The central cholinergic system plays an important role in the regulation of cognitive function. In early stage of patients of MCI and AD there are obviously degeneration in cholinergic neurons, and major clinical manifestations is learning and memory function impairment. To inject a certain dose of hyoscine hydrobromide can cause memory impairment of rats, then we experiment them with diving platform. Ethology data of the rats showed, to take orally certain dose of KYG can cause error response latency reduced. The bio-chemical detection showed the possible echanism is to improve the content of BDNF in rat brain tissue to protect neurons against damage by hyoscine hydrobromide, and reduce the activity of ACHE, increase the activity of CHAT to make more ACH involved in nerve conduction in brain tissue, improving the ability of learning and memory. At the same time, through the cell experiments in vitro, it also showed that KYG can increase the content of Ach and Cha T, suppress the activity of Ach E in human neuroblastoma cell caused by okadaic acid, slow down the decomposition of ACH, speed up the information transmission, strengthen memory capacity. The results of these studies and behavioral data showed that, KYG is to reduce the learning and memory impairment caused by hyoscine hydrobromide through the regulation of cholinergic system balance.Mitochondrial DNA decided to oxidative stress signal response including mitochondrial function and reactive oxygen species and so on. Reactive oxygen species in physiological concentrations play an important role in cell signal transduction and defense of external injury, but too much ROS can damage nucleic acid, protein, lipid, resulting in a corresponding increase in oxidation products, and partial oxidation products of them can be further modified nucleic acids, aggravate neuronal damage. The neurons with pathological changes be not replaced by new neurons is a key factor affecting the recovery of cognitive function. The hippocampus is the most important organization regulation of cognition, and the neuronal regeneration in this part plays an important role in restoration of various CI. By affording exogenous antioxidants or oxygen free radical scavenger can promote the regeneration of neuron. Oxidative stress is believed to be associated with many neurodegenerative diseases, such as one of the important factors in the pathogenesis of AD and MCI in disease. Through the clinical study of AD patients, it showed that OS have significant effects on dynamic balance of calcium and apoptosis, and is one of the important mechanism in the pathogenesis of AD. Antioxidant, free radical scavenger can improve the protective effect on nerve cells. MDA and the activity of SOD is a classic evaluation indicators of oxidative stress.Intraperitoneal injection of sodium nitrite to rats can not only cause memory impairment, but also can trigger ROS in brain tissue, resulting in the increase of oxidation products, and damaging the neuron to make memory consolidation disturbance. Through the experimental platform research, the study showed the occurred error response latency prolonged in the model group, the content of MDA in hippocampus of the brain increased, the activity of SOD decreased, the content of NO and the activity of NOS was significantly increased. While the KYG in a certain dose can improve these symptoms, can reduce the effects of oxidative stress on memory impairment in rat model by sodium nitrite, remove the accumulation of oxidation products in cells, activate the activity of antioxidant enzymes, prevent damage to the nervous system by oxidative stress reaction.The ligation operation to hibateral arteria carotis communis can form acute oxidative stress, decrease blood flow, form local Inflammatory reaction, damage neuronal, result in Va D. Through the Morris water maze we test the behavior and the change of content of 5-HT, NE, DA in brain of rats by ligation operation to hibateral arteria carotis communis. Morris water maze experiment is to test the ability of spatial learning and memory in rats by recording the number of crossing the withdraw platform. With the increase of the number of training days, rats escape latency time showed a decreasing trend in every group. Training to fourth days, there was a difference in latency time. The learning and memory ability of rats through the ligation operation to hibateral arteria carotis communis may be decline, or dementia, while KYG can relief sequel caused by Va D to a certain extent. In the brain tissue of rats in KYG group, the content of 5-HT and DA increased, the content of NE dropped, that suggesting traditional Chinese medicine is a multi-target, multi-way to improve body functions.In Chinese medicine CI will be belong to dementia disease. Dementia is consciousness disease showed main clinical manifestations with dull and stupid caused by pulp to reduce brain subsides, patrons disuse. It occurred morely in the elderly, especially in older people. The location of disease is in the brain, closed to heart, liver, spleen and kidney. KYG is made up with Polygonum multiflorum, ginseng and other traditional Chinese medicines, and has the effect of nourishing liver and kidney, benefiting qi and nourishing blood, phlegm and begin to understand, and tranquilize the mind and promote the intelligence. We adopted the orthogonal experimental design method, TLC, UV spectrophotometry, infrared spectrometry, optimized and validated the part of the extraction process parameters, and survey and evaluate 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside which was the active ingredients in Polygonum multiflorum in preparation by using HPLC, to control the quality of the preparation.In order to verify the antioxidant properties of KYG, we adopted the experiment on cells in vitro to study whether KYG had protective effect on the damage of SH-SY5 Y cells induced by OKA. OKA is a phosphatase inhibitor of serine / threonine, which involved in protein phosphorylation, and make cell phosphorylation avishly, and is the preferred material of cytotoxicity in vitro cell oxidative stress damage model. In this experiment, we use the high concentration of Okada to induce MDA accumulation with SH-SY5 Y cells, resulting in cells was damaged by oxidative stress. Under the light microscope, we could see a large number of cells to be death, the cell survival rate decreased significantly, the apoptosis rate was significantly increased. At the same time, activity of SOD decreased in these cells, which resulting in more serious oxidative damage. But a certain dose of KYG can eliminate the peroxidation product accumulation in cells, activate the activity of antioxidant enzymes, lighten oxidative stress induced by OKA.According to the experimental results in vivo and in vitro, we found that KYG can significantly improve the cognitive dysfunction of rat model induced by hyoscine hydrobromide and sodium nitrite, and impairment of spatial memory caused by Va D. This effect may be related to inhibition of activity of ACh E and regulation of oxidative stress. Therefore, KYG can be used as an alternate drug for the treatment of neurodegeneration diseases, to improve and treat MCI and AD with superiority of traditional Chinese medicine as combining multi-target, multi link, with multi mechanism.