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POSSIBLE PARTICIPATION OF NITRIC OXIDE IN THR PATHOGRNESIS UNDERLYING ISCHEMIC CEREBRAL DAMAGE

一氧化氮可能参与缺血性脑损伤的发病机制

基本信息

批准号：
07457323
负责人：
MATSUI Toru
金额：
$ 3.26万
依托单位：
SAITAMA MRDICAL SCHOOL
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457323/
关键词：
NITRIC OXIDE NITRIC OXIDE SYNTHASE NITRIC OXIDE SYNTHASE INHIBITOR CEREBRAL ISCHEMIA PERMANENT ISCHEMIA TEMPORARY ISCHEMIA OCCLUSION OF MIDDLE CEREBRAL ARTERY RATS 一酸化窒素合成酵素阻害薬一酸化窒素合成阻害薬脳血流電極法脳浮腫

项目摘要

Although it remains to be yet whether nitric oxide (NO) is neurotoxic or neuroprotective, our recent study elucidated the narrow therapeutic window of LNA,Nw-nitro-L-arginine, against occlusion of the middle cerebral artery in rats (MCAo). Our result was consistent with the report that partial blockade of NO synthase (NOS) was beneficial to the treatment of MCAo in mice. Furthermore, the recent study, using mice genetically deficient in neuronal cNOS,demonstrared that neuronal NO mediated neuronal cell damage due to a focal brain ischemia. Besides these indirect findings, we directly measured the temporal alterations in cerebral NO concentration ([NO]) and NOS activity in rats subjected to permanent and tranaient focal cerebral isehemia and the effects of LNA on both [NO] and ischemic brain damage were examined.[NO]in the ischemic core increased biphasically at 15-45 min.and at 180-240 min.after MCAo. Restoration of blood flow afler 2 hr of MCAo caused a rapid depression and a subsequent small increase of [NO] at 70-100 min. However, NOS activity of P2 and S2 was at the high level during not only the increasing phase but the decreased phase of [NO]. Administration of LNA in permanent and transient MCAo diminished the changes in [NO] and reduced infarct volume by about 70% at 4 hr post-ischemia.The phenomenon that [NO] decreased when NOS activity in the ischemic cortex remained at the high level may suggest that overproduced NO may rapidly react with superoxide anion to form peroxynitrite anion. We conclude that these heterogeneous elevations in [NO] are important as to the induction of brain damage due to permanent and transient focal cerebral ischemia.

尽管一氧化氮 (NO) 是否具有神经毒性或神经保护作用尚不清楚，但我们最近的研究阐明了 LNA（Nw-硝基-L-精氨酸）针对大鼠大脑中动脉闭塞 (MCAo) 的狭窄治疗窗。我们的结果与部分阻断 NO 合酶 (NOS) 有利于治疗小鼠 MCAo 的报道一致。此外，最近的研究使用神经元 cNOS 遗传缺陷的小鼠，证明神经元 NO 介导局灶性脑缺血引起的神经元细胞损伤。除了这些间接发现之外，我们还直接测量了遭受永久性和暂时性局灶性脑缺血的大鼠脑NO浓度（[NO]）和NOS活性的时间变化，并检查了LNA对[NO]和缺血性脑损伤的影响。缺血核心中的[NO]在MCA后15-45分钟和180-240分钟双相增加。 MCAo 2 小时后血流恢复导致 [NO] 快速下降，随后在 70-100 分钟时小幅增加。然而，P2和S2的NOS活性不仅在[NO]增加期而且在[NO]减少期都处于高水平。在永久性和短暂性MCAo中给予LNA可减少[NO]的变化，并在缺血后4小时使梗塞体积减少约70%。当缺血皮质中的NOS活性保持在高水平时[NO]减少的现象可能表明过量产生的NO可能与超氧阴离子快速反应形成过氧亚硝酸根阴离子。我们得出的结论是，[NO] 的这些异质性升高对于诱导永久性和短暂性局灶性脑缺血引起的脑损伤很重要。