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Prolonged suppression of brain nitric oxide synthase activity by 7-nitroindazole protects against cerebral hypoxic–ischemic injury in neonatal rat

  • Akira Ishida
    Footnotes
    Affiliations
    Department of Neurology, Johns Hopkins University, School of Medicine, and The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA

    The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA
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  • William H. Trescher
    Correspondence
    Corresponding author. Tel.: +1-410-502-9049; fax: +1-410-502-8942
    Affiliations
    Department of Neurology, Johns Hopkins University, School of Medicine, and The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA

    The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA
    Search for articles by this author
  • Mary S. Lange
    Affiliations
    The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA
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  • Michael V. Johnston
    Affiliations
    Department of Neurology, Johns Hopkins University, School of Medicine, and The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA

    Department of Pediatrics, Johns Hopkins University, School of Medicine, and The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA

    The Kennedy Krieger Research Institute, 707 North Broadway, Baltimore, MD 21205, USA
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  • Author Footnotes
    1 Present address: Department of Pediatrics, Akita University School of Medicine, 1-1-1 Hondo, Akita-shi, Akita 010, Japan.

      Abstract

      Nitric oxide mediates glutamate-induced excitotoxicity associated with cerebral hypoxia–ischemia through production in the brain by several isoforms of nitric oxide synthase (NOS). We examined the influence of the selective neuronal NOS inhibitor, 7-nitroindazole (7-NI), on brain NOS activity and its neuroprotective effects against cerebral hypoxic–ischemic injury in the postnatal day (PND) 7 rat. In the first set of experiments, 7-NI (50 mg/kg) administered intraperitoneally (i.p.) transiently inhibited NOS activity to 40% below the vehicle control level at 1 h after injection (P<0.001, analysis of variance (ANOVA)). In contrast, 7-NI (100 mg/kg, i.p.) inhibited NOS activity to 56% below the control level at 1 h with prolonged suppression of NOS activity at 3, 6, 9 and 12 h after injection. Two-factor ANOVA revealed an overall effect on NOS activity of 7-NI treatment (P<0.001) and time after injection (P<0.001). In the second set of experiments, 7-NI (50, 100 mg/kg) or an equal volume of vehicle was administered after unilateral carotid artery ligation, but 30 min before hypoxia in PND 7 rats. 7-NI (100 mg/kg) significantly protected against cerebral hypoxic–ischemic injury (100 mg/kg of 7-NI, 1.7±1.0% damage; control, 8.7±1.6%,P<0.05). 7-NI administered 15 min after cerebral hypoxia–ischemia was not neuroprotective. The data suggest that the protective effect of 7-NI is dose dependent, and is related to the duration of suppressed NOS activity.

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