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Survey of peroxynitrite scavengers and its application for pathophysiolgy

过氧亚硝酸盐清除剂的研究及其在病理生理学中的应用

基本信息

批准号：
10557247
负责人：
OHKUMA Seitaro
金额：
$ 7.17万
依托单位：
KAWASAKI MEDICAL SCHOOL
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

In this research project, we have attempted to survey scavengers specific for peroxynitrite and to apply them to investigation for clarification of pathophysiological role of peroxynitrite in neuronal cell injury. Prior to the survey of peroxynitrite scavengers, we have investigated the roles of peroxynitrite in release of neurotransmitters such as γ-aminobutyric acid (GABA) and acetylcholine and its mechanisms, because we attempts to use the potential of peroxynitrite to induce neurotransmitter release as a tool to confirm the activity of its scavengers.We confirmed that peroxynitrite enhanced the release of GABA and acetylcholine from mouse cerebral cortical neurons in primary culture. Using this experimental system we have examined mechanisms for peroxynitrite-evoked GABA release. Peroxynitrite-induced GABA release was abolished by inhibitors of neuronal membrane depolarization, suggesting the activity of peroxynitrite to depolarize neuronal membrane. Peroxynitrite also increased Ca … More ^<2+> influx into neurons. Each of nifedipine and ω-agatoxin VIA (ω-ATX), inhibitors specific for L- and P/Q-type voltage-dependent Ca^<2+> channels (VDCCs) respectively, inhibited significantly GABA release by peroxynitrite and the concomitant presence of these inhibitors completely abolished the influx induced by peroxynitrite, whereas ω-conotoxin GVIA (ω-CTX), an inhibitor for N-type VDCCs affected no changes. From these results it is concluded that peroxynitrite induced GABA release consequent to opening L- and P/Q-type VDCCs and did not modify the function of N-type VDCCs.Hydroxyl radical scavengers also facilitated peroxynitrite-evoked GABA release and this inhibitory action of hydroxyl radical formed from peroxynitrite during its degradation is due to its inhibition of L-type VDCCs, indicating hydroxyl radical modifies the apparent peroxynitrite-induced neurotransmitter release. In addition, the activity of peroxynitrite to induce Ca^<2+> influx into the neurons by MnTBPA, a known scavenger for peroxynitrite. In present, we are trying to survey scavengers for peroxynitrite using the experimental system described above for checking activities of candidates to abolish peroxynitrite activity. Less

在这个研究项目中，我们试图调查特定的过氧亚硝酸根清除剂，并将它们应用于调查的病理生理作用的过氧亚硝酸根在神经细胞损伤的澄清。在研究过氧亚硝酸根清除剂之前，我们研究了过氧亚硝酸根在γ-氨基丁酸（GABA）和乙酰胆碱等神经递质释放中的作用及其机制，因为我们试图利用过氧亚硝酸盐诱导神经递质释放的潜力作为一种工具来证实其清除剂的活性，我们证实过氧亚硝酸盐增强小鼠大脑皮层神经元GABA和乙酰胆碱的释放在初级培养中。使用这个实验系统，我们已经研究过亚硝酸盐诱发的GABA释放的机制。过氧亚硝基阴离子诱导的GABA释放被神经元膜去极化抑制剂所消除，表明过氧亚硝基阴离子具有去极化神经元膜的活性。过氧亚硝酸盐也增加Ca ...更多信息 ^<2+>流入神经元。硝苯地平（nifedipine）和ω-芋螺毒素VIA（ω-ATX）（分别为L型和P/Q型电压依赖性Ca^2+通道（VDCCs）特异性抑制剂）均能显著抑制过氧亚硝酸根引起的GABA释放，同时存在这两种抑制剂可完全消除过氧亚硝酸根引起的GABA内流，而N型VDCCs抑制剂ω-芋螺毒素GVIA（ω-CTX）则无此作用。结果表明，过氧亚硝基阴离子能诱导GABA释放，但并不改变N型VDCCs的功能，过氧亚硝基阴离子能诱导GABA释放，羟自由基清除剂也能促进过氧亚硝基阴离子诱导的GABA释放，其抑制作用是由于过氧亚硝基阴离子能抑制L型VDCCs，表明羟基自由基改变了表观过氧亚硝酸盐诱导的神经递质释放。此外，MnTBPA（一种已知的过氧亚硝酸根清除剂）诱导Ca^2+内流进入神经元的过氧亚硝酸根活性。目前，我们正试图使用上述实验系统调查过氧亚硝酸根的清除剂，以检查候选物的活性，以消除过氧亚硝酸根活性。少