Pharmaceutical Studies Aiming at Nerve Cell Degeneration Repairing and Protecting Agent

神经细胞退变修复保护剂的药学研究

基本信息

批准号：
12480175
负责人：
FUKUYAMA Yoshiyasu
金额：
$ 5.25万
依托单位：
Tokushima Bunri University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

This research project has been performed toward development of nerve cell degeneration repairing and/or protecting agent from novel neurotrophic natural products. The following results have been obtained.(1) Two types of serum-free primary neuronal cultures have been established. Screening natural products by using these cultured neurons nine new neurite outgrowth promoting active substances and six new neuroprotective substances have been found. One of them, in particular, could protect β-amyloid-induced death of neurons.(2) Neurotrophic substance, honokiol, mastigophorenes A and B, and americanol A and isoamericanol A were synthesized by palladium-catalyzed reactions and/or HRP-catalyzed oxidative coupling. On the other hand, synthesis of plagiochin A was succeeded by intramolecular Stille-Kelly reaction. Now, our effort has directed to the synthesis of merrilactone A based on palladium-catalyzed sequential Stille-Heck reaction.(3) Pharmacological studies on honokiol-induced neurite outgrowth promoting activity were carried out by using several inhibitors. As results, RTK and MAPK signal pathway was indicated to be involved in neurite outgrowth mediated by honokiol. Additionally, Fluo 3 imaging analysis of honokiol showed that it can increase cytoplasmic free Ca^<2+> through a PLC-mediated pathway. It is worthy of note that magnolol, a analog of honokiol, could dose-dependently prevent the decrease of density of the CA1 in the hippocampus of senescence-accelerated mice (SAM).

本研究项目旨在开发新型神经营养天然产物的神经细胞变性修复和/或保护剂，取得了以下成果：(1)建立了两种类型的无血清原代神经元培养物的筛选。通过使用这些培养的神经元，发现了九种新的神经突生长促进活性物质和六种新的神经保护物质，其中一种特别可以保护β-淀粉样蛋白诱导的神经元死亡。（2）神经营养物质，和厚朴酚，通过钯催化反应和/或HRP催化氧化偶联合成了massigophorenes A和B，以及americanol A和isoamericanol A。另一方面，通过分子内Stille-Kelly反应成功合成了plagiochin A。基于钯催化序贯Stille-Heck反应合成merrilactone A。(3)药理研究使用多种抑制剂进行了和厚朴酚诱导的神经突生长促进活性，结果表明RTK和MAPK信号通路参与了和厚朴酚介导的神经突生长，此外，和厚朴酚的Fluo 3成像分析表明它可以增加细胞质游离。 Ca ^ 2+ 通过PLC介导的途径值得注意的是，厚朴酚（和厚朴酚的类似物）可以剂量依赖性地防止细胞密度的降低。衰老加速小鼠 (SAM) 海马体中的 CA1。