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).

该研究项目是为了开发神经细胞变性修复和/或保护剂免受新型神经营养天然产物的发展。（1）已经建立了两种无血清原发性神经元培养物。通过使用这些培养的神经元筛选天然产物，发现六种新的神经蛋白产物促进活性物质和六种新的神经保护物质。尤其是其中一种可以保护神经营养物质，honokiool，乳脂烯酸A和B，以及甲基A和Isoamericanol A合成的神经营养性物质，由Palladium-Catalyzed反应和/或HRP-hrp-cataly-Cataly-coupling合成。另一方面，通过分子内静脉反应成功地合成了疟原虫A的合成。现在，我们的努力已针对钯催化的顺序静止 - 螺旋反应的合成a的合成。（3）使用多种抑制剂进行了有关Honokiol诱导的神经蛋白神经蛋白神经蛋白促进生长活性的药理研究。结果，RTK和MAPK信号途径被指出参与由Honokiol介导的神经差异。此外，Fluo 3对Honokiol的成像分析表明，它可以通过PLC介导的途径增加细胞质游离Ca^<2+>。值得注意的是，木诺（Honokio的类似物）可以依赖性地剂量阻止敏感加速小鼠海马中Ca1的密度降低（SAM）。