Persistent neurochemical changes in neonatal piglets after hypoxia–ischemia and resuscitation with 100%, 21% or 18% oxygen

Jantzie, Lauren L.; Cheung, Po-Yin; Obaid, Laila; Emara, Marwan; Johnson, Scott T.; Bigam, David L.; Todd, Kathryn G.

doi:10.1016/j.resuscitation.2007.10.008

Cited by 20 publications

(13 citation statements)

References 36 publications

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“…In this context, the 9½ h follow-up time after the HI injury may be too short a time to reveal clear changes at the histopathological level in our model, and consequently it is difficult to indubitably predict the effect of HI at later time points. Usually, after HI and resuscitation cell death continue to progress for days and even weeks [29] and neurochemical changes may persist for several days [30]. The long-term neurological deficit must be assessed to determine the efficacy of therapeutic interventions in asphyxiated neonates and ideally, it should be evaluated together with short-term mortality and neurofunctional deficit [31].…”

Section: Discussionmentioning

confidence: 99%

Resuscitation of Newborn Piglets. Short-Term Influence of FiO2 on Matrix Metalloproteinases, Caspase-3 and BDNF

et al. 2010

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BackgroundPerinatal hypoxia-ischemia is a major cause of mortality and cerebral morbidity, and using oxygen during newborn resuscitation may further harm the brain. The aim was to examine how supplementary oxygen used for newborn resuscitation would influence early brain tissue injury, cell death and repair processes and the regulation of genes related to apoptosis, neurodegeneration and neuroprotection.Methods and FindingsAnesthetized newborn piglets were subjected to global hypoxia and then randomly assigned to resuscitation with 21%, 40% or 100% O2 for 30 min and followed for 9 h. An additional group received 100% O2 for 30 min without preceding hypoxia. The left hemisphere was used for histopathology and immunohistochemistry and the right hemisphere was used for in situ zymography in the corpus striatum; gene expression and the activity of various relevant biofactors were measured in the frontal cortex. There was an increase in the net matrix metalloproteinase gelatinolytic activity in the corpus striatum from piglets resuscitated with 100% oxygen vs. 21%. Hematoxylin-eosin (HE) staining revealed no significant changes. Nine hours after oxygen-assisted resuscitation, caspase-3 expression and activity was increased by 30–40% in the 100% O2 group (n = 9/10) vs. the 21% O2 group (n = 10; p<0.04), whereas brain-derived neurotrophic factor (BDNF) activity was decreased by 65% p<0.03.ConclusionsThe use of 100% oxygen for resuscitation resulted in increased potentially harmful proteolytic activities and attenuated BDNF activity when compared with 21%. Although there were no significant changes in short term cell loss, hyperoxia seems to cause an early imbalance between neuroprotective and neurotoxic mechanisms that might compromise the final pathological outcome.

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Section: Discussionmentioning

confidence: 99%

Resuscitation of Newborn Piglets. Short-Term Influence of FiO2 on Matrix Metalloproteinases, Caspase-3 and BDNF

et al. 2010

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“…The present investigation builds on these findings and, to the best of our knowledge, we are the first to report that in the critical acute time period after H/R, administration of NAC maintains cerebral amino acid profiles. These data are particularly important in light of previously published studies showing that certain resuscitation practices chronically alter amino acid neurochemistry likely contributing to neuronal damage [33] .…”

Section: Discussionmentioning

confidence: 89%

“…In these immature neural networks, inhibitory circuits are underdeveloped while excitation predominates and glutamate receptors, ion channels and transporters are expressed at high levels [43] . Thus, alterations of the amino acids glutamate, aspartate, alanine, glycine and GABA could negatively impact the trajectory of brain development, disrupt the delicate balance between excitation and inhibition in the immature CNS, and alter signal transduction and synaptogenesis [29,33] . In the present investigation, we observed significant and regionally dependent changes in seven amino acids after H/R.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Amino Acid Profiles after Hypoxia-Reoxygenation and N-Acetylcysteine Treatment in the Newborn Piglet

et al. 2009

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Background: Neonatal hypoxia-ischemia (HI) is a common clinical occurrence. Recently, much evidence has been gathered to suggest that oxygen free radicals are implicated in the pathogenesis of hypoxia-reoxygenation injury through the initiation and propagation of toxic cascades including glutamate excitotoxicity and the manifestation of post-HI neurologic disorders. Following HI, excessive free radicals are formed and antioxidant defenses are diminished. N-acetylcysteine (NAC) is a clinically available antioxidant and has been previously shown to reduce oxidative stress and scavenge free radicals in multiple models of brain injury. Objectives: Using an acutely instrumented swine model of neonatal hypoxia-reoxygenation, the objective of the present study was to examine the neurochemical effects of NAC administration in 5 brain regions exquisitely vulnerable to severe hypoxia. Methods: In a blinded fashion, newborn piglets (1–4 d, 1.4–2.2 kg) were block randomized into surgical sham (SHAM), hypoxic control (HC) and NAC-treated (H-NAC) groups. Both HC and H-NAC piglets were subject to 2 h of alveolar hypoxia (paO₂ = 20–40 mm Hg) and then resuscitated with 100% O₂for 1 h followed by 21% for an additional 3 h. Results: Our results show that two hours of severe hypoxemia causes metabolic acidosis and significant changes in cerebral amino acids including glutamate, aspartate and alanine, in all brain regions investigated including the cortex, basal ganglia and thalamus. The administration of NAC 10 min into the reoxygenation period and subsequently continued as an infusion, maintains post-resuscitation amino acid neurochemistry at the levels observed in SHAM piglets. Conclusions: In newborn piglets that have sustained brain injury related to hypoxia/reoxygenation, the administration of NAC does not disrupt cerebral amino acid balance and maintains cerebral amino acid homeostasis.

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“…Piglet models have been very useful in the study of resuscitation, hemodynamics, hypoxic-ischemic encephalopathy and term brain injury[24,39]. Piglets can also be delivered preterm via Cesarean section between 0.79 and 0.98 GA, with 0.70 GA being approximately equivalent to a 25–27 week GA human.…”

Section: Species: Large or Small Mammalsmentioning

confidence: 99%

Preclinical Models of Encephalopathy of Prematurity

Jantzie

Robinson

2015

Dev Neurosci

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Encephalopathy of prematurity (EoP) encompasses the central nervous system (CNS) abnormalities associated with injury from preterm birth. Although rapid progress is being made, limited understanding exists of how cellular and molecular CNS injury from early birth manifests as the myriad of neurological deficits in children who are born preterm. More importantly, this lack of direct insight into the pathogenesis of these deficits hinders both our ability to diagnose those infants who are at risk in real time and could potentially benefit from treatment and our ability to develop more effective interventions. Current barriers to clarifying the pathophysiology, developmental trajectory, injury timing, and evolution include preclinical animal models that only partially recapitulate the molecular, cellular, histological, and functional abnormalities observed in the mature CNS following EoP. Inflammation from hypoxic-ischemic and/or infectious injury induced in utero in lower mammals, or actual prenatal delivery of more phylogenetically advanced mammals, are likely to be the most clinically relevant EOP models, facilitating translation to benefit infants. Injury timing, type, severity, and pathophysiology need to be optimized to address the specific hypothesis being tested. Functional assays of the mature animal following perinatal injury to mimic EoP should ideally test for the array of neurological deficits commonly observed in preterm infants, including gait, seizure threshold and cognitive and behavioral abnormalities. Here, we review the merits of various preclinical models, identify gaps in knowledge that warrant further study and consider challenges that animal researchers may face in embarking on these studies. While no one model system is perfect, insights relevant to the clinical problem can be gained with interpretation of experimental results within the context of inherent limitations of the chosen model system. Collectively, optimal use of multiple models will address a major challenge facing the field today - to identify the type and severity of CNS injury these vulnerable infants suffer in a safe and timely manner, such that emerging neurointerventions can be tailored to specifically address individual reparative needs.

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Persistent neurochemical changes in neonatal piglets after hypoxia–ischemia and resuscitation with 100%, 21% or 18% oxygen

Cited by 20 publications

References 36 publications

Resuscitation of Newborn Piglets. Short-Term Influence of FiO2 on Matrix Metalloproteinases, Caspase-3 and BDNF

Resuscitation of Newborn Piglets. Short-Term Influence of FiO2 on Matrix Metalloproteinases, Caspase-3 and BDNF

Cerebral Amino Acid Profiles after Hypoxia-Reoxygenation and N-Acetylcysteine Treatment in the Newborn Piglet

Preclinical Models of Encephalopathy of Prematurity

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