Effects of Selective Nitric Oxide Synthase Inhibition on IGF-1, Caspases and Cytokines in a Newborn Piglet Model of Perinatal Hypoxia-Ischaemia

Peeters-Scholte, Cacha; Koster, Johanna G.; Tweel, Evelyn van den; Blomgren, Klas; Hamers, Nicole; Zhu, Changlian; Buul‐Offers, Sylvia van; Hagberg, Henrik; Bel, Frank van; Heijnen, Cobi J.; Groenendaal, Floris

doi:10.1159/000069045

Cited by 19 publications

(14 citation statements)

References 33 publications

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“…Inhibition of NOS utilizing different classes of selective inhibitors is a promising strategy for neuroprotection after perinatal hypoxia-ischemia [1,4,[12][13][14]. In the present study, the decrease in the number of nNOS immunoreactive cortical neurons in hypoxic newborn piglet brains following administration of 7-NINA is consistent with the abating effect rendered by this selective nNOS inhibitor on the levels of nNOS and iNOS proteins [6].…”

Section: Discussionsupporting

confidence: 82%

Effect of 7-Nitroindazole Sodium on the Cellular Distribution of Neuronal Nitric Oxide Synthase in the Cerebral Cortex of Hypoxic Newborn Piglets

et al. 2006

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Cerebral hypoxia results in generation of nitric oxide (NO) free radicals by Ca(++)-dependent activation of neuronal nitric oxide synthase (nNOS). The present study tests the hypothesis that the hypoxia-induced increased expression of nNOS in cortical neurons is mediated by NO. To test this hypothesis the cellular distribution of nNOS was determined immunohistochemically in the cerebral cortex of hypoxic newborn piglets with and without prior exposure to the selective nNOS inhibitor 7-nitroindazole sodium (7-NINA). Studies were conducted in newborn piglets, divided into normoxic (n = 6), normoxic treated with 7-NINA (n = 6), hypoxic (n = 6) and hypoxic pretreated with 7-NINA (n = 6). Hypoxia was induced by lowering the FiO(2) to 0.05-0.07 for 1 h. Cerebral tissue hypoxia was documented by decrease of ATP and phosphocreatine levels in both the hypoxic and 7-NINA pretreated hypoxic groups (P < 0.01). An increase in the number of nNOS immunoreactive neurons was observed in the frontal and parietal cortex of the hypoxic as compared to the normoxic groups (P < 0.05) which was attenuated by pretreatment with 7-NINA (P < 0.05 versus hypoxic). 7-NINA affected neither the cerebral energy metabolism nor the cellular distribution of nNOS in the cerebral cortex of normoxic animals. We conclude that nNOS expression in cortical neurons of hypoxic newborn piglets is NO-mediated. We speculate that nNOS inhibition by 7-NINA will protect against hypoxia-induced NO-mediated neuronal death.

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Section: Discussionsupporting

confidence: 82%

Effect of 7-Nitroindazole Sodium on the Cellular Distribution of Neuronal Nitric Oxide Synthase in the Cerebral Cortex of Hypoxic Newborn Piglets

et al. 2006

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“…every 4h. 10,11 Our current study supports that the full dose range of 0.1 to 1.0 mg/ kg 2-IB is safe; the 0.2 mg/kg/dose shows the most promising short-term outcome data in our piglet model of perinatal HI. Limitations of this study include the treatment with 2-IB immediately postinsult, and the potential bias caused by the exclusion of mildly affected piglets.…”

Section: Discussionsupporting

confidence: 76%

Short-Term Dose–Response Characteristics of 2-Iminobiotin Immediately Postinsult in the Neonatal Piglet After Hypoxia-Ischemia

Björkman

Ireland

Fan

et al. 2013

Stroke

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P erinatal hypoxia-ischemia (HI) is a significant cause of neonatal brain injury. Neonatal animal models of HI show that excessive production of nitric oxide (NO), mediated by nitric oxide synthases (NOS), play an important role in the pathogenesis of neuronal injury after HI in the neonate.1,2 Three isoforms of NOS exist: the constitutively expressed neuronal NOS, endothelial NOS, and the inducible NOS. In vitro studies have shown that selective inhibition of neuronal NOS and inducible NOS can be achieved by the NOS inhibitor 2-iminobiotin (2-IB). 3To transition treatment to the human term neonate, it is important to know the dose-response effect of 2-IB to identify the optimal dose to be given after perinatal HI. The aim of this study was to determine the dose-response characteristics of 2-IB in a preclinical animal model of perinatal HI and to establish the most effective dose (range) for future clinical trials. This study was performed in our piglet model of inhalational HI, which is clinically, electrophysiologically, and neuropathologically comparable with the term born human neonate. The HI insult was performed in term neonatal piglets (n=47) as previously described 5 ; 6 animals served as sham-operated controls. HI piglets were randomly assigned to blinded treatment with vehicle or 2-IB at 0.1, 0.2, or 1 mg/kg/dose i.v. immediately post-HI and dosing repeated every 4 h until 20 h (6 doses in total). aEEG background pattern, presence of epileptic activity, and neurobehavior were scored. 6At 48 h postinsult animals were euthanized and tissue analyzed for caspase-3 activity, tyrosine nitration, and histology (see the onlineonly Data Supplement). ResultsIn total, 47 piglets were subjected to HI; 16 piglets were only mildly affected (continuous normal voltage at 30 min post-HI; see the online-only Data Supplement for examples) and excluded from further analysis. Of the remaining 31 piglets, 10 were vehicle-treated, 7 received 0.1 mg/kg/dose, 9 received 0.2 mg/kg/dose, and 5 received 1.0 mg/kg/dose. There was no difference in birth weight, postnatal age, pH, arterial BE, PO 2 , PCO 2, duration of hypotension, heart rate, or temperature between treatment groups (see the online-only Data Supplement).Background and Purpose-To determine the optimal dose of 2-iminobiotin (2-IB) for the treatment of moderate to severe asphyxia in a neonatal piglet model of hypoxia-ischemia. Methods-Newborn piglets were subjected to a 30-minute hypoxia-ischemia insult and randomly treated with vehicle or 2-IB (0.1 mg/kg, 0.2 mg/kg, or 1.0 mg/kg). aEEG background and seizure activity were scored after hypoxia-ischemia every 4 h until 24 h and at 48 h and neurobehavioral scores were obtained. Brain tissue was collected and processed for analysis of caspase-3 activity, histology, and tyrosine nitration. Results-A dose range of 0.1 to 1.0 mg/kg/dose of 2-IB improved short-term outcome as demonstrated by an increased survival with a normal aEEG and decreased nitrotyrosine staining in the 2-IB-treated animals, indicating decreased cellular...

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“…38 Pharmacological inhibition nNOS and iNOS reduced nitrotyrosine formation 38 and was demonstrated to be neuroprotective. 72 Oxidative stress, including production of NO and peroxynitrite, is considered to induce mainly necrotic cell death but may also be involved in apoptosis. 73 The developing brain may be Crude cytosolic fractions from naïve P5, P9, P21 and P60 (n ¼ 5 for each age) control animals (Control), and from animals subjected to HI, were assayed for their ability to cleave a fluorogenic peptide substrate (DEVD), reflecting the caspase-3-like activity.…”

Section: Discussionmentioning

confidence: 99%

The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia–ischemia

et al. 2004

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Unilateral hypoxia-ischemia (HI) was induced in C57/BL6 male mice on postnatal day (P) 5, 9, 21 and 60, corresponding developmentally to premature, term, juvenile and adult human brains, respectively. HI duration was adjusted to obtain a similar extent of brain injury at all ages. Apoptotic mechanisms (nuclear translocation of apoptosis-inducing factor, cytochrome c release and caspase-3 activation) were several-fold more pronounced in immature than in juvenile and adult brains. Necrosis-related calpain activation was similar at all ages. The CA1 subfield shifted from apoptosis-related neuronal death at P5 and P9 to necrosis-related calpain activation at P21 and P60. Oxidative stress (nitrotyrosine formation) was also similar at all ages. Autophagy, as judged by the autophagosome-related marker LC-3 II, was more pronounced in adult brains. To our knowledge, this is the first report demonstrating developmental regulation of AIF-mediated cell death as well as involvement of autophagy in a model of brain injury.

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Effects of Selective Nitric Oxide Synthase Inhibition on IGF-1, Caspases and Cytokines in a Newborn Piglet Model of Perinatal Hypoxia-Ischaemia

Cited by 19 publications

References 33 publications

Effect of 7-Nitroindazole Sodium on the Cellular Distribution of Neuronal Nitric Oxide Synthase in the Cerebral Cortex of Hypoxic Newborn Piglets

Effect of 7-Nitroindazole Sodium on the Cellular Distribution of Neuronal Nitric Oxide Synthase in the Cerebral Cortex of Hypoxic Newborn Piglets

Short-Term Dose–Response Characteristics of 2-Iminobiotin Immediately Postinsult in the Neonatal Piglet After Hypoxia-Ischemia

The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia–ischemia

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