The Effect Of Xiao Zhi Tang On Sustained Hyperlipidemia Induced Early Neurogenesis Impairment Prior To Dementia:an Experimental Study Of Biological Markers

Objective:To observe the effect and mechanism of sustained exposure to hyperlipidemia on early biological markers ofneurogenesis impairment related to dementia, and to explore the effect of Xiao Zhi Tang, atorvastatin and metformin treatment.Methods:Male Ldlr-/-mice on a genetic background of C57BL/6J were fed with a high fat/high cholesterol diet for10weeks and became hyperlipidemic. Then the Ldlr-/-mice were assigned randomly into the model group, metformin treatment group, atorvastatin treatment group and Xiao Zhi Tang treatment group (8mice in each group) and fed with the high-fat/high cholesterol diet for another10weeks. In treatment groups, metformin, atorvastatin and Xiao Zhi Tang were given to the Ldlr-/-mice respectively. A control group with8C57BL/6J mice received no treatment and was fed with a normal diet throughout the study. At the end of the study, blood and organ samples of all mice were collected for analysis.Result:1) Ldlr-/-mice in the model group had decreased brain weight on body weight (P<0.05), lower nerve growth factor (NGF) level (P<0.01) in brain tissue, and microglia-dominant focal gliocyteproliferation with neuron loss.2) The decrease of NGF level in brain tissue was positively correlated with serum GLP-1(P<0.05), serum eNOS, brain weight on body weight, and ADPN in brain tissue (P<0.01), and was negatively correlated with serum ET-1and body weight at endpoint (P<0.05).3) Atorvastatin and Xiao Zhi Tang could significantly raise the NGF level in brain tissue (P<0.01), and decrease the microglia-dominant focal gliocyteproliferation in brain. Metformin (P<0.05) and Xiao Zhi Tang (P<0.01) could significantly raise the vitamin D receptor (VDR) level in brain tissue.Conclusion:1) A10-week sustained exposure to hyperlipidemia could induce early biological markers of neurogenesis impairment related to dementia in young adult mice. Treatment against hyperlipidemia should be an important part of the primary prevention against dementia.2) The mechanism of early neurogenesis impairment in this study was correlated with insulin resistance and dysfunction of endothelial vasodilation and vasoconstriction, and prior to the existence of inflammation and atherosclerosis.3) Atorvastatin and Xiao Zhi Tang could improve the early neurogenesis impairment induced by sustained exposure to hyperlipidemia and showed potential for primary prevention against dementia4) The TCM Xiao Zhi Tang showed many advantages from potential to clinical use for primary prevention against dementia, such as working on more therapeutic targets than atorvastatin and metformin, preservation of beta-cell function, and assured safety and tolerance and patient compliance.