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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12480175/
• 关键词: neurotrophic substance; primary cultured neuron; neurite outgrowth; neuroprotection; calcium ion; sesquiterpene; aromatic compound; protein kinase; 神経細胞突起伸展作用; 神経栄養因子; ラット大脳皮質神経培養; ジテルペン; パラジウム; β-アミロイド; 酸化酵素; 神経突起伸展物質; 合成

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).

本研究项目旨在从新型神经营养天然产物中开发神经细胞变性修复和/或保护剂。取得了以下结果。(1)两种类型的无血清原代神经元培养已经建立。利用培养的神经元筛选天然产物，发现9种新的促进神经突起生长的活性物质和6种新的神经保护物质，其中1种对β-淀粉样蛋白诱导的神经元死亡具有保护作用。(2)通过钯催化的反应和/或HRP催化的氧化偶联合成神经营养物质和厚朴酚、乳香烯A和B以及美洲醇A和异美洲醇A。另一方面，通过分子内Stille-Kelly反应成功合成了plagiochin A。目前，我们的工作主要是基于钯催化的Stille-Heck反应合成merrilactone A。(3)通过使用几种抑制剂对和厚朴酚诱导的神经突起生长促进活性进行了药理学研究。结果表明，RTK和MAPK信号通路参与了和诺明介导的神经突起生长。此外，和厚朴的Fluo 3成像分析显示，它可以通过PLC介导的途径增加细胞质游离Ca^2+。厚朴酚能剂量依赖性地阻止加速衰老小鼠海马CA 1区密度的降低。

项目成果

Yoshiyasu Fukuyama et al.: "Merrilactone A, a Novel Neurotrophic Sesquiterpene Dilactone from Illicium merrillianum"Tetrahedron Letters. 41, 32. 6111-6114 (2000)

Yoshiyasu Fukuyama 等人：“Merrilactone A，一种来自八角茴香的新型神经营养倍半萜双内酯”四面体快报。

Yoshiyasu Fukuyama: "Vibsane-type Diterpenes from Taiwanese Viburnum odoratissimum"Chem.Pharm.Bull.. 49・2. 242-245 (2001)

Yoshiyasu Fukuyama：“来自台湾荚莲属植物的Vibsane型二萜”Chem.Pharm.Bull.. 49・245 (2001)。

Yoshiyasu Fukuyama: "The First Total Syhnthesis and Neurotrophic Activitiy of Clusiparalicoline A, a Prenylated and Geranylated Biaryl from Clusia paralicola"Tetrahedron Letters. 43. 6919-6923 (2002)

Yoshiyasu Fukuyama：“Clusiparalicoline A（一种来自 Clusia paralicola 的异戊二烯化和香叶基化联芳基）的首次全合成和神经营养活性”四面体快报。

Yoshiyasu Fukuyama et al.: "New Seco-prezizaane-type Sesquiterpenes, Jiadifenin and 1, 2-Dehydroneomajucin with Neurotrophic Activity from Illicium jiadifengpi"J. Nat. Prod.. 65, (4). 527-531 (2002)

Yoshiyasu Fukuyama等人：“来自八角茴香的新型Seco-prezizaane型倍半萜、Jiadifenin和1, 2-DeHydroneomajucin具有神经营养活性”J.

Yoshiyasu Fukuyama: "Three Novel Sesquiterpenes from the Pericarps of Illicium merrillianum"Chem.Pharm.Bull.. 48・5. 301-303 (2000)

Yoshiyasu Fukuyama：“来自八角茴香果皮的三种新型倍半萜”Chem.Pharm.Bull.. 48・5（2000）。