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Mechanism of pharmacological action of nootropics in the hippocampus

海马促智药的药理作用机制

基本信息

批准号：
02454496
负责人：
KURAISHI Yasushi
金额：
$ 3.9万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-02454496/
关键词：
nootropics hippocampus mossy fiber CA3 synaptosome C kinase glutamate bifemelane binding site

项目摘要

The use-dependent strengthening of a synaptic efficacy is known as a long-term potentiation. The long-term potentiation that occurs in the hippocampus is thought to be a cellular mechanisms associated with learning and memory. Since the long-term potentiation observed in the mossy fiber-CA3 system is potentiated by low concentrations of brain function potentiating drugs, it is conceivable that synapse between mossy fibers and CA3 pyramidal cells is one of common sites of actions of these drugs. Therefore, this project was conducted as a step to elucidate the mechanisms of pharmacological actions of brain function potentiating drugs in the hippocampus and the following results have been gotten.1. Bifemelane, a brain function potentiating drug, increased the high K^+ evoked release of L-glutamate from the mossy fiber terminals in the hippocampus of the guinea-pig. Such an increase may be at least partly mediated with the activation of protein kinase C in the mossy fiber terminals, as it was blocked by a kinase inhibitor, H-7, and bifemelane produced the translocation of protein kinase C from cytosol to membrane in the mossy fiber terminals. Bifemelane did not produce an increase in the evoked release of L-glutamate from nor translocation of protein kinase C in conventional synaptosomes that dose not contain mossy fiber terminals.2. There were specific binding sites for [^3H]bifemelane in the hippocampus of the guinea-pig and the density of such binding sites were higher in the CA3 than in the CAl. A high affinity binding sites for [^3H]bifemelane may not be monoamine uptake sites, as they were observed in the presence of imipramine. The specific binding of [^3H]bifemelane was inhibited by bifemelane at 1-1000 nM, but not by vinpocetine, indeloxazine, idebenone, piracetam and Ca hopatenate.

突触功效的使用依赖性加强被称为长时程增强。海马中的长时程增强被认为是与学习和记忆相关的细胞机制。由于在苔藓纤维-CA 3系统中观察到的长时程增强被低浓度的脑功能增强药物增强，可以想象苔藓纤维和CA 3锥体细胞之间的突触是这些药物的共同作用部位之一。因此，本课题旨在阐明脑功能增强药物在海马中的药理作用机制，取得了以下研究结果. Bifemelane是一种脑功能增强药物，它能增加高钾离子诱发的L-谷氨酸从豚鼠海马苔藓纤维末端的释放。这种增加可能至少部分介导的苔藓纤维末端中的蛋白激酶C的激活，因为它被阻断的激酶抑制剂，H-7，和bifemelane产生的蛋白激酶C的易位从胞质到膜的苔藓纤维末端。在不含苔藓纤维末端的传统突触体中，Bifemelane并没有引起L-谷氨酸的诱发释放增加，也没有引起蛋白激酶C的移位。在豚鼠的海马中存在[^3H]bifemelane的特异性结合位点，并且这种结合位点在CA 3中的密度高于在CA 1中的密度。[^3H]bifemelane的高亲和力结合位点可能不是单胺摄取位点，因为它们是在丙咪嗪存在下观察到的。1-1000 nM的双苯美兰可抑制[^3H]双苯美兰的特异性结合，但长春新碱、茚地嗪、艾地苯醌、吡拉西坦和霍帕酸钙则不抑制。