| Kai-Xin-San(KXS)is a traditional Chinese medicinal formula composed of Ginseng Radix et Rhizoma,Polygalae Radix,Acori Tatarinowii Rhizoma,and Poria for relieving major depressive disorder and Alzheimer’s disease in traditional Chinese medicine(TCM)clinics.In the long-term clinical practice,according to the needs of syndrome differentiation and treatment,KXS has formed a variety of compatibility.At the same time,based on the previous research of our group,we screened the active components in the cell model and animal model,and combined the optimal compatibility ratio for the development of new drugs,and evaluated its efficacy and safety.Through a large number of Chinese and foreign literature research,it can be found that central nervous system inflammation is closely related to the incidence of depression.Microglia in the brain of patients with depression are overactivated,releasing inflammatory factors and causing damage to neurons.In this paper,from the animal level,through the construction of chronic stress depression animal model,to evaluate the optimal ratio of KXS to regulate the effect of central nervous system inflammation and antidepressant.At the same time,the specific mechanism of KXS against central nervous system inflammatory injury was evaluated by constructing microglia activation model and neuron inflammatory injury model at the cellular level.The paper is divided into four chapters,the contents are as follows:Ⅰ.Literature research.1.This paper summarizes the pathogenesis of depression from two aspects of modern medicine and traditional Chinese medicine.2.The inflammation of central nervous system was reviewed from the mechanism of central nervous system inflammation and the regulatory substances of central nervous system inflammation.3.Based on the antidepressant mechanism of KXS and the regulation of central nervous system inflammation by the flavor components of KXS,the antidepressant mechanism of KXS was reviewed.Ⅱ.Study on the utility evaluation and mechanism of KXS in regulating central nervous system inflammation and antidepressant animal model.1.Antidepressant Behavioral Evaluation of KXS in regulating Central nervous system inflammation.In order to investigate the effect of KXS on regulating central nervous system inflammation and antidepressant,the chronic stress model of mice was established,starting with three behavioral indexes:the consumption of sucrose and the immobile time in FST and TST.It was found that all the effective compounds of KXS had good antidepressant effect,among which D-652 seemed to have a stronger effect.2.Evaluation of biochemical Indexes of KXS in regulating Central nervous system inflammation and antidepressant.In order to explore the specific mechanism of KXS in regulating inflammation of central nervous system,a mouse model of chronic stress was established,and its effects on the release of inflammatory factors and activation of microglia in hippocampus of mice were observed.The results showed that KXS could inhibit the activation of microglia.In order to explore the mechanism of inflammatory signal transduction pathway,the regulation of KXS on central nervous system inflammation is related to the down-regulation of TLR4 and inhibition of NF-кB activation.TUNEL staining showed that after the treatment of KXS,the hippocampal neurons of mice were apoptotic,the expression of Caspase-3 protein was up-regulated,and the positive rate of apoptosis decreased.Ⅲ.The cell model utility evaluation and mechanism of KXS regulating central nervous system inflammation and antidepressant.1.Study on the mechanism of KXS based on microglia in regulating the expression of inflammatory factors in central nervous system.In order to investigate the anti-inflammatory effect and specific mechanism of KXS,a model of inflammatory factor expression in microglia activated by LPS was established.It was found that KXS could inhibit the activation of TLR4/IKK/NF-кB signal pathway,prevent NF-кB protein from entering the nucleus to recognize the corresponding DNA sequence,and then inhibit the coding and release of inflammatory cytokines.TLR4,as a receptor for microglia to detect the changes of microenvironment in the brain,is regulated by PI3K/Akt/FoXO1 pathway.When cells are stimulated by LPS,the activation of PI3K/Akt is inhibited.After FoXO1 enters the nucleus to recognize the corresponding DNA sequence,it encodes the expression of TLR4 protein on microglia,which can be inhibited by KXS.At the same time,TLR4 and NF-кB entry blockers were selected to block the expression of inflammatory factors in microglia,and it was confirmed that the release of inflammatory factors regulated by NF-кB was related to TLR4/IKK/NF-кB signal pathway.2.Study on the Mechanism of NF-кB against neuronal inflammatory injury based onNeuron.In order to investigate the mechanism of KXS against neuron inflammatory injury,a neuron inflammatory injury cell model was established.Apoptosis occurred after injury,and this phenomenon was inhibited after administration.Furthermore,the mechanism of action was studied,and it was found that KXS could inhibit neuronal apoptosis by promoting the activation of PI3K/Akt signal pathway and inhibiting the expression of apoptotic protein Caspase-3.Ⅳ.Evaluation and mechanism of antidepressant effect and mechanism of KXS in the regulation of central nervous system inflammation and antidepressant.1.Study on the animal model of Central nervous system inflammation and antidepressant regulated by the combination of functional substances of KXS.In order to investigate the antidepressant effect of the combination of functional substances of KXS,the chronic stress model of mice was established,starting with three behavioral indexes:SPT,FST and TST.It was found that the effective compounds of KXS could alleviate the depression-like behavior of mice.By detecting the expression of inflammatory factors in the hippocampus of mice,it was found that the combination of functional substances of KXS could down-regulate the expression of inflammatory factors,and the combination of functional substances of KXS could regulate the inflammation of central nervous system.2.Study on the combination of functional substances of KXS in the Regulation and Regulation of neuronal inflammatory injury.In order to study the anti-inflammatory effect of the effective compounds of KXS,a model of microglial inflammatory factor expression activated by LPS was constructed,and the expression of inflammatory factor was down-regulated after administration.At the same time,the neuron inflammatory injury cell model was constructed,and it was found that the viability of the damaged cells could be restored after the combination of KXS.This study reveals that KXS regulates central nervous system inflammation and gives full play to the material basis of neuroprotective and antidepressant effects,which provides theoretical support for the development of new drugs of KXS. |
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