Molecular and Chemical Neuropathology

, Volume 26, Issue 2, pp 107–157 | Cite as

Nitric oxide synthase in cerebral ischemia

Possible contribution of nitric oxide synthase activation in brain microvessels to cerebral ischemic injury
  • Toshiaki Nagafuji
  • Masakazu Sugiyama
  • Toru Matsui
  • Atsushi Muto
  • Shigetaka Naito
Original Articles


The results of our continuing studies on the role of nitric oxide (NO) in cellular mechanisms of ischemic brain damage as well as related reports from other laboratories are summarized in this paper. Repetitive ip administration ofN G-nitro-L-arginine (L-NNA), a NO synthase (NOS) inhibitor, protected against neuronal necrosis in the gerbil hippocampal CA1 field after transient forebrain ischemia with a bell-shaped response curve, the optimal dose being 3 mg/kg. Repeated ip administration of L-NNA also mitigated rat brain edema or infarction following permanent and transient middle cerebral artery (MCA) occlusion with a U-shaped response. The significantly ameliorative dose-range and optimal dose were 0.01–1 mg/kg and 0.03 mg/kg, respectively. Studies using a NO-sensitive microelectrode revealed that NO concentration in the affected hemisphere was remarkably increased by 15–45 min and subsequently by 1.5–4 h after MCA occlusion. Restoration of blood flow after 2 h-MCA occlusion resulted in enhanced NO production by 1–2 h after reperfusion. Administration of L-NNA (1 mg/kg, ip) diminished the increments in NO production during ischemia and reperfusion, leading to a remarkable reduction in infarct volume. In brain microvessels obtained from the affected hemisphere, Ca2+-dependent constitutive NOS (cNOS) was activated significantly at 15 min, and Ca2+-independent inducible NOS (iNOS) was activated invariably at 4 h and 24 h after MCA occlusion. Two hour reperfusion following 2 h-MCA occlusion caused more than fivefold increases in cNOS activity with no apparent alterations in iNOS activity. Thus, we report here based on available evidence that there is good reason to think that NOS activation in brain microvessels may play a role in the cellular mechanisms underlying ischemic brain injury.

Index Entries

Nitric oxide (NO) neuronal constitutive nitric oxide synthase (N-cNOS) endothelial constitutive nitric oxide synthase (E-cNOS) inducible nitric oxide synthase (iNOS) forebrain ischemia focal cerebral ischemia middle cerebral artery (MCA) occlusion nitric oxide (NO)-sensitive microelectrode brain microvessels 


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Copyright information

© Humana Press Inc 1995

Authors and Affiliations

  • Toshiaki Nagafuji
    • 1
  • Masakazu Sugiyama
    • 1
  • Toru Matsui
    • 2
  • Atsushi Muto
    • 1
  • Shigetaka Naito
    • 1
  1. 1.CNS Diseases Research Unit, Fuji-Gotemba Research LaboratoriesChugai Pharmaceutical Col., Ltd.ShizuokaJapan
  2. 2.Department of NeurosurgerySaitama Medical Center/SchoolSaitamaJapan

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