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

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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.