Study On The Pharmacodynamics And Mechanism Of Panax Ginseng C.A. Meyer In Treating The Deficiency Of Vital Energy Dementia Rats

With the extension of human life span and the rapid aging of the population,senile dementia has become a key public health problem worldwide,placing a huge economic burden on society.According to TCM theory,dementia is a common disease in the elderly characterized by phlegm and blood stasis masking the brain orifices,blocking the brain collaterals,and finally leading to cognitive impairment,which is the deficiency of Qi.Modern pharmacological studies suggest that the cause of dementia may be aging and reduced oxygen free radical scavenging ability caused by brain function degeneration and nerve cell damage,which in turn leads to the occurrence of dementia.As an important tonic drug,Panax ginseng C.A.Meyer not only has the effects of tonifying blood and invigorating Qi,improving immunity,but also has a significant effect in reducing inflammation,anti-oxidation,and protecting nerve cells.Therefore,Panax ginseng C.A.Meyer is considered as a potential drug for the treatment of senile dementia.However,due to the complex composition of Panax ginseng C.A.Meyer and the possible interaction between different components,its material basis and mechanism of action are not clear,which limits its application.Based on this,in this study,we established a rat model of deficiency of vital energy dementia with both qi deficiency syndrome and pathological state of dementia according to the characteristics and mechanism of senile dementia.The ginsenosides and ginseng polysaccharides,the main pharmacodynamic components of Panax ginseng C.A.Meyer,were used as research objects.On the one hand,pharmacodynamics,metabolomics,gut microbial genomics and other methods were used to systematically explore the efficacy and mechanism of action of each active component of Panax ginseng C.A.Meyer on deficiency of vital energy dementia rats.On the other hand,targeted network pharmacology and pharmacokinetic-pharmacodynamic correlation analysis methods were used to deeply validate its mechanism of action and preliminarily explain its pharmacodynamic material basis.The main research content includes the following aspects:1.Establishment and evaluation of rat model of deficiency of vital energy dementiaA rat model of deficiency of vital energy dementia was established by combined administration of aluminum trichloride(AlCl₃)and D-galactose(D-Gal)combined with exhaustive swimming,and the model was also evaluated from the dual perspectives of qi deficiency related indicators(serum biochemical indicators,blood routine,immune organ index,endurance,body weight,excreta,appearance of signs,etc.)and dementia related indicators(behavioral,histopathological,brain tissue biochemical indicators,etc.).The results indicated that the rat model of deficiency of vital energy dementia successfully replicated the pathophysiological state of qi deficiency and dementia and could be used for subsequent studies.In addition,urine metabolomics studies further showed that phenylalanine,tyrosine and tryptophan metabolism,taurine and hypotaurine metabolism,TCA cycle and pyrimidine metabolism and other related pathways closely related to neurotransmitters and body energy metabolism are closely related to deficiency of vital energy dementia.2.Pharmacodynamic evaluation of the components of Panax ginseng C.A.Meyer in treating the deficiency of vital energy dementia ratsThe pharmacodynamic effects of active composition of Panax ginseng C.A.Meyer were assessed from the dual perspectives of qi deficiency related indicators and dementia related indicators.It was found that each components showed a certain therapeutic effect.In terms of improving spatial cognition and learning ability in dementia rats of qi deficiency type,all groups had more significant effects except the total ginsenosides+total ginseng polysaccharides(1:1)mixture.In the conditions of improving dementia related pathological,ginsenosides and ginseng polysaccharides can not only effectively protect neuronal cells,alleviate protein deposition and hyperphosphorylation,inhibit stress expression of microglia,and inhibit neurotoxic substance production,but also repair oxidative stress damage and cholinergic defects in brain tissue,so as to achieve a therapeutic effect of improving spatial learning and memory ability,with ginsenosides having a more significant effect.In terms of improving qi deficiency indicators,ginsenosides and ginseng polysaccharides can enhance endurance and regulate body inflammation by regulating immunoglobulins,increasing blood cell viability,increasing body weight and immune organ quality,which has a significant effect on improving the immune capacity of deficiency of vital energy dementia rats,with the effect of ginseng polysaccharides being more significant.The above efficacy reflected a better comprehensive therapeutic effect in the aqueous extract of ginseng.In terms of overall efficacy,ginsenosides and ginseng polysaccharides did not show a synergistic effect,but they showed a synergistic effect in repairing oxidative stress.3.Metabolomics Study on the Mechanism of the components of Panax ginseng C.A.Meyer in treating the deficiency of vital energy dementia ratsMetabolic profiles of urine,feces,and serum samples from rats in each group were collected based on UPLC-Q-TOF-MSE(ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry)technology to construct metabolic pathway perturbation maps.According to the regulatory effect of Panax ginseng C.A.Meyer active components on differential endogenous metabolites in 14metabolic pathways,it can be found that ginsenosides and ginseng polysaccharides promote the production of substances or compounds that can protect nerves by related metabolic pathways by affecting tryptophan metabolism,phenylalanine and tyrosine metabolism,forming neuroprotective effects;and play a role in repairing oxidative stress damage by affecting bile acid biosynthesis,arachidonic acid metabolism,fatty acid biosynthesis and metabolism.And the aqueous extract of ginseng and the mixture of ginsenosides+ginseng polysaccharides also had a comprehensive regulatory effect in the above pathways.4.The mechanism of the components of Panax ginseng C.A.Meyer in treating the deficiency of vital energy dementia rats through microbiome-gut-brain axisThe behavioral parameters,biochemical parameters of brain tissue,and targeted quantitative results of differential endogenous metabolites of rats in each group were correlated with intestinal bacteria.The results showed that the active components of Panax ginseng C.A.Meyer could callback the abnormal values of neurotransmitters,bile acids,and unsaturated fatty acids in deficiency of vital energy dementia rats,and regulate the imbalanced intestinal bacteria.Combined with the results of correlation analysis,it can be seen that ginsenosides and ginseng polysaccharides interact with intestinal bacteria in deficiency of vital energy dementia rats by acting on the microme-gut-brain axis bidirectional communication system,acting on the central nervous system to regulate cerebral metabolic activity,regulate neurotransmitter metabolic disorders,enhance the ability of deficiency of vital energy dementia rats,scavenge oxygen free radicals,reduce neurotoxicity,repair damaged cranial nerves,and protect nerve cells.Among them,the aqueous extract of ginseng has a good effect in regulating neurotransmitters,bile acids,unsaturated fatty acids and gut microbiome;the mixture of ginsenosides+ginseng polysaccharides(1:1)not only has the effect in regulating the above indicators,but also can act synergistically to regulate Taurine,Norepinephrine,Eicosapentaenoic acid and Docosahexaenoic acid.5.Correlation analysis of pharmacokinetics and pharmacodynamics of ginsenoside treating the deficiency of vital energy dementia ratsThe targeted network pharmacology method was used to establish the blood component-disease target-signaling pathway network map.It is speculated that the pharmacodynamic components of ginsenosides in the treatment of deficiency of vital energy dementia rats can act on VEGFA,FGF2,IL2,AKT1,MAPK1,MAPK8,MAPK14 and other targets.Involved in MAPK,PI3K-Akt,TNF,and other signaling pathways to play a regulatory role.By monitoring the dynamic changes of pharmacodynamic components of ginsenoside and differential endogenous metabolites and the constructed correlation analysis results,it can be seen that Ginsenoside Rb₂,Ginsenoside Rc and Ginsenoside Re not only have better drug absorption and utilization rate in the deficiency of vital energy dementia rats,but also can restore the abnormal values of Ursodeoxycholic acid,Taurocholic acid,Glycocholic acid and Arachidonic acid within 48 hours after administration.The pharmacodynamic components of ginsenosides also have a certain regulatory effect on other differential endogenous metabolites,reflecting the mechanism of ginsenosides in regulating the abnormal metabolism of neurotransmitters,bile acids,and unsaturated fatty acids through multiple targets,repairing damaged nerves,and activating the immune system.The above experimental results systematically explain the pharmacodynamic material basis and mechanism of ginsenoside in the treatment of deficiency of vital energy dementia rats.In summary,in this paper,the rat model of deficiency of vital energy dementia was established by combined administration of AlCl₃ and D-Gal combined with exhaustive swimming,and the model was evaluated by multiple indicators.Taking urine,feces and serum samples as the research objects,through metabolomics and intestinal bacteria genomics research,it is found that Panax ginseng C.A.Meyer can protect nerve cells,repair oxidative stress damage and enhance the immune capacity of the body by acting on the bidirectional communication of microbe-intestine-brain axis.A network diagram of blood component-disease target-signaling pathway was established using targeted network pharmacology,and by monitoring the dynamic changes of pharmacodynamic components of ginsenosides and differential endogenous metabolites and establishing correlation analysis,the key targets and information pathways of ginsenosides in the treatment of dementia rats with qi deficiency were found and their pharmacodynamic material basis was preliminarily explained.The study combined TCM theory and modern analytical technical means to explore the pharmacodynamics and mechanism of Panax ginseng C.A.Meyer in the treatment of deficiency of vital energy dementia rats in depth and systematically.It not only comprehensively explains the pharmacodynamics and multi-target synergistic mechanism of Panax ginseng C.A.Meyer in the treatment of deficiency of vital energy dementia rats,but also provides an effective methodological reference for the systematic study of the mechanism of action of traditional Chinese medicine.