Therapeutic Effect And Preliminary Pharmacokinetics Of Phenolic Acid Analogs On Abdominal Aortic Aneurysm

Objective:To establish a complete evaluation system of abdominal aortic aneurysm model,and based on this,to study the efficacy mechanism and preliminary pharmacokinetics of candidate compounds.Methods:This study explored the angiotensin II?AngII?-induced apolipoprotein gene deletion mice(ApoE^-/-),AngII and benzopyrene,respectively,from the aspects of the mechanism of abdominal aortic aneurysm and the existing research basis.Pancreatic elastase and calcium chloride induced C57 mice and other four routes to prepare an animal model of aortic aneurysm.Based on the laboratory research on the effects of phenolic acids in Salvia miltiorrhiza on abdominal aortic aneurysm,this study also conducted pharmacodynamic evaluation and preliminary pharmacokinetic studies on the three polyphenolic acid analogues and evaluated their pharmacodynamics.In a trypsin-induced mouse abdominal aortic aneurysm model,hematoxylin-eosin staining and lichen red staining were used to evaluate the vascular structure;immunohistochemistry was used to examine inflammatory cell infiltration;gelatin zymography was used to examine matrix metalloproteinases?MMP-2 and MMP-9?levels.The preliminary pharmacokinetic study used LC-MS/MS method to determine the blood concentration of three kinds of polyphenolic acid analogues in rats.It is hoped to find candidate compounds with good efficacy and absorption.Results:Firstly,four animal models were evaluated from various aspects such as the rate of molding,vascular pathology and clinical similarity,time-consuming and cost-consuming,and finally the mouse model induced by pancreatic elastase was determined for subsequent study.The mice were intragastrical administrated with 60mg/kg RA,RA-6,and RA-8.The RA-8 significantly reduced the diameter of the abdominal aortic aneurysm and protected the integrity of the elastin layer compared with the other two compounds;It was found that RA-8 significantly inhibited the infiltration of macrophages in abdominal aortic aneurysms and inhibited the activity of MMP-9.After clarifying the different effects of RA,RA-6 and RA-8 on abdominal aortic aneurysms,the pharmacokinetic parameters of RA,RA-6 and RA-8 were initially examined.Conclusion:RA-8 showed good therapeutic effect on abdominal aortic aneurysm compared with RA and RA-6.It has good prospects for development.At the same time,RA-8 andRA-6related pharmacokinetics wereobtainedin the pharmacokinetics experiment.