基于替米沙坦抗神经源性炎症的候选化合物Tek-1的药理学研究-药理学专业论文.docxVIP

基于替米沙坦 基于替米沙坦抗神经源性炎症的候选化合物 Tek-1 的药理学研究 英文摘要 PAGE PAGE III IV IV The pharmacological research of Tek-1 relevance to anti-neuroinflammation, a candidate compound based on Telmisartan Abstract Objective: Upon the important role of AT1 receptor and PPARγ receptor in modulating anti-oxidative damage and neuroprotection, we designed and acquired the candidate compound Tek-1 through the modification of biphenyl carboxylic acid unit. In this project, we identified the dual pharmacology characteristics based on AT1 receptor and PPARγ receptor; furtherly, in vivo we evaluated the ameliorative effect of Tek-1 on learning and memory dysfunction in AD mouse model induced by beta-amyloid (Aβ); we investigated the role of Tek-1 on regulating activated microglia closely related to the neuro-inflammation and signal transduction mechanism in order to obtain new structure AT1 antagonist with better PPARγ receptor agonistic bioactivity. Methods: First, through radioligand binding assay on rat vascular smooth muscle cells, calcium mobilization HTS assay and PPARγ responsive-element-luciferase reporter assay, we evaluated the AT1 receptor affinity of Tek-1, and antagonistic activity as well as PPARγ agonistic activity respectively; Second, in Alzheimer’s disease mouse model of C57BL/6J mice induced by introcerebroventricular injection of Aβ1-42, Telmisartan (1, 3 mg/kg) and Tek-1(1, 3, 10 mg/kg) were continuously administered for 4 weeks. Then through the Morris water maze and the novel objects recognition test, we investigated the effect of Telmisartan and Tek-1 on the spatial and nonspatial learning and memory abilities in AD mouse model. And the concentration of Interleukin (IL-6) and monocyte chemotactic protein-1 (MCP-1) in brain were explored using ELISA; Third, we established BV-2 microglia inflammatory model stimulated by bacterial lipopolysaccharide (LPS) in vitro, and then cells were treated with Telmisartan (0.1-10μM) and Tek-1 (0.1-10μM), or in the presence of Telmisartan