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

Akira Ishida, William Trescher, Mary S. Lange, Michael V. Johnston

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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.

Original languageEnglish (US)
Pages (from-to)349-354
Number of pages6
JournalBrain and Development
Volume23
Issue number5
DOIs
StatePublished - Aug 22 2001

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Nitric Oxide Synthase
Wounds and Injuries
Brain
Brain Hypoxia-Ischemia
Injections
Analysis of Variance
7-nitroindazole
Nitric Oxide Synthase Type I
Neuroprotective Agents
Carotid Arteries
Statistical Factor Analysis
Ligation
Glutamic Acid
Nitric Oxide
Protein Isoforms

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Neurology

Cite this

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title = "Prolonged suppression of brain nitric oxide synthase activity by 7-nitroindazole protects against cerebral hypoxic-ischemic injury in neonatal rat",
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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Prolonged suppression of brain nitric oxide synthase activity by 7-nitroindazole protects against cerebral hypoxic-ischemic injury in neonatal rat. / Ishida, Akira; Trescher, William; Lange, Mary S.; Johnston, Michael V.

In: Brain and Development, Vol. 23, No. 5, 22.08.2001, p. 349-354.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Ishida, Akira

AU - Trescher, William

AU - Lange, Mary S.

AU - Johnston, Michael V.

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N2 - 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.

AB - 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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