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

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-精氨酸对大鼠大脑中动脉闭塞(MCAO)的治疗窗口狭窄。我们的结果与部分阻断一氧化氮合酶(NOS)有利于治疗小鼠MCAO的报道一致。此外，最近的研究，使用神经元型cNOS基因缺陷的小鼠，证实了神经元型NO介导局灶性脑缺血引起的神经细胞损伤。除了这些间接结果外，我们还直接测定了永久性和短暂性局灶性脑缺血大鼠脑内NO浓度([NO])和NOS活性的时间变化，并观察了LNA对[NO]和缺血性脑损伤的影响。大脑中动脉阻塞2小时后恢复血流，导致快速下降，随后在70-100分钟时[NO]略有升高。而P2和S2的NOS活性在[NO]增高期和减低期均处于较高水平。在永久性和短暂性MCAO模型中应用LNA可减少脑缺血后4h[NO]的变化，并使脑梗塞体积缩小约70%。当缺血皮质中的NOS活性维持在较高水平时，[NO]下降的现象可能提示过量的NO可能与超氧阴离子迅速反应生成过氧亚硝酸根阴离子。我们的结论是，在永久性和短暂性局灶性脑缺血所致的脑损伤中，[NO]的这种异质性升高是重要的。

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.