Role of Nitric Oxide in Ischemic Brain Damage

Abstract

Our results on the role of nitric oxide (NO) in cellular mechanisms of ischemic brain damage are as follows. (1) Repeated i.p. administration of N G-nitro-L-argininc (L-NNA) mitigated rat brain edema or infarction following permanent middle cerebral artery (MCA) occlusion at a dosage of 0.01–1 mg/kg. (2) In brain microvessels obtained from the affected hemisphere, Ca2+-dependent constitutive nitric acid synthase (NOS) (E-c-NOS) was activated consistently at an early stage. On the other hand, Ca2+-independent inducible NOS (i-NOS) was activated at 4h and 24h after MCA occlusion. (3) In the cerebral cortex, only Ca2+-dependent constitutive NOS (N-c-NOS) was activated during the first 4h of MCA occlusion in rats. (4) A2-h reperfusion following a 2-h MCA occlusion caused a significant increase in E-c-NOS and N-c-NOS activity without any apparent alterations in i-NOS activity. (5) NO concentration in the affected hemisphere was remarkably increased at 15–30 min and subsequently at 3–4 h after MCA occlusion. (6) Restoration of blood flow for 2h after a 2-h MCA occlusion resulted in an enhanced NO concentration at 1–1.5 h after recirculation. (7) Administration of L-NNA (1 mg/kg i.p.) diminished the increments of NO concentration during ischemia and reflow, leading to its neuroprotection. Although it remains to be determined whether NO is neurotoxic or neuroprotective in cerebral ischemia, these results directed us to the conclusion that NOS activation in brain microvessels and cerebral cortex may play a role in the cellular mechanisms underlying ischemic brain injury.