Effect of Graded Hypoxia on Brain Cell Membrane Injury in Newborn Piglets

DiGiacomo, J. E.; Pane, Carmela R.; Gwiazdowski, Steven; Mishra, Om P.; Delivoria‐Papadopoulos, Maria

doi:10.1159/000243527

Cited by 64 publications

(29 citation statements)

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“…Na + ,K+-ATPase activity was significantly reduced during cerebra l hypoxia alone (group 3). As in our previous study (20), the magnitude of the decrease in Na+ ,K+-ATPase activity correlated with the magnitude of the decrease in PCr/Pi in each animal. However, in the animals subjected to a hyperglycemic glucose clamp before and during hypoxia, Na+,K+-ATPase activity was preserved at control levels even .. though PCr/p i was reduced, regardless of the magnitude of the change in PCr/Pi.…”

Section: Resultssupporting

confidence: 84%

“…We have shown in the fetus and newborn that cerebral hypoxia leads to alterations in cell membrane structure and function as demonstr ated by increas ed brain cell membrane lipid peroxidation and decreased activity of the cerebral Na+,K+-A'TPase (18)(19)(20). Based on previous studies that demonstrated that hyperglycemia improved surviva l and preserved brain structure in the newborn during hypoxia/ischemia, we hypothesized that hyperglycemia might also act to preserve brain cell membran e structure and function during cerebral hypoxia.…”

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confidence: 99%

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Brain Cell Membrane Function during Hypoxia in Hyperglycemic Newborn Piglets

et al. 1995

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To test the hypothesis that acute hyperglycemia reduces changes in cell membrane structure and function during cerebral hypoxia in the newborn, brain cell membrane Na+,K+-A'TPase activity and levels of membrane lipid peroxidation products were measured in four groups of anesthetized, ventilated newborn piglets: normoglycemia/normoxia (control, group 1, n = 12), hyperglycemia/normoxia (group 2, n = 6), untreated hypoxia (group 3, Jl = 10), and hyperglycemialhypoxia (group 4, n = 7). Hyperglycemia (blood glucose concentration 20 mmollL) was induced using the glucose clamp technique. The hyperglycemic glucose clamp was maintained for 90 min before onset of hypoxia and throughout the period of hypoxia. Cerebral tissue hypoxia was induced in groups 3 and 4 by reducing fraction of inspired oxygen for 60 min and was documented by a decrease in the ratio of phosphocreatine to inorganic phosphate as measured using 31P-nuclear magnetic resonance spectroscopy. Blood glucose concentration during hypoxia in hyperglycemic hypoxic animals was 20.7 ± 1.2 mmol/L, compared with 10.3 ± 1.7 mmol/L in untreated hypoxic piglets (p < 0.05). Peak blood lactate concentrations were not significantly different between the two hypoxic groups (8.4 ± 2.8 rnmol/L versus 7.8 ± 1.6 mmollL). In cerebral cortical membranes prepared from the In the brain, an hyp oxic-ischemic insult leads to acc umu latio n of lactate, tissue ene rgy dep letion and aci dosis, and neuro na l necrosis (1-4). Because glucose serves as the major energy so urce for the brain (5, 6), a nu mbe r of stud ies have investigated the role of changes in glucose con centra tion in mo difying the effec ts of ce rebral hypoxia/ischem ia. In adult an imal mo dels, outco me afte r ce reb ral ischemia was improved by mild hypoglycemia, and neuro log ic da mage was more extensive in animals that were hypergl ycemic during or after the insult (2,7,8). Th ese findings have been attributed to the effects of intrace llular lac tic acidosis res ulting from increased anae robic glycolysis in hypergl ycemic anim als (7, 9, 10). untreated animals, cerebral tissue hypoxia caused a 25% reduction in Na+,K+-ATPase activity compared with normoxic controls and an increase in conjugated dienes and fluorescent compounds, markers of lipid peroxidation. In contrast, Na+,K+-ATPase activity and levels of lipid peroxidation products in hyperglycemic hypoxic animals were not significantly different from the values in control normoxic animals. These data suggest that in the newborn piglet model acute hyperglycemia reduces hypoxia-induced brain cell membrane dysfunction. (Pediatr Res 37: 133-139, 1995) Abbrevia tions NMR , nuclear magnetic resonance Fi0 2 , fraction of inspired oxygen PCr, phosphocreatine Pi, inorganic phosphate PCrlPi, ratio of phosphocreatine to inorganic phosphate MAUP, mean arterial blood pressure GSH, reduced glutathione ANOVA, analysis of variance D25W, dextrose 25% wt/vol in water Studies by Myers and coworkers (11 ,12) suggested that hypergl ycemia also increased hypoxic/ische m...

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Brain Cell Membrane Function during Hypoxia in Hyperglycemic Newborn Piglets

et al. 1995

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“…16 Because of its similarity in overall shape, gyral pattern, distribution of gray and white matter, and growth pattern to human infants, the piglet brain has been used extensively to model human development. 6,16,17,19,49 The response of the piglet to hypoxia and ischemia appears to parallel that in human infants; cerebral blood flow and metabolism are similar, and the piglet brain matures in a similar manner with respect to myelination and electrical activity. 11,16,40,50 The size of the pig brain is ideally suited for clinically relevant biomechanical modeling of human head trauma, including both focal and inertial injuries involving gray and white matter.…”

Section: Discussionmentioning

confidence: 96%

Maturation-dependent response of the piglet brain to scaled cortical impact

Duhaime¹,

Margulies²,

Durham³

et al. 2000

Journal of Neurosurgery

146

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Object. The goal of this study was to investigate the relationship between maturational stage and the brain's response to mechanical trauma in a gyrencephalic model of focal brain injury. Age-dependent differences in injury response might explain certain unique clinical syndromes seen in infants and young children and would determine whether specific therapies might be particularly effective or even counterproductive at different ages.Methods. To deliver proportionally identical injury inputs to animals of different ages, the authors have developed a piglet model of focal contusion injury by using specific volumes of rapid cortical displacement that are precisely scaled to changes in size and dimensions of the growing brain. Using this model, the histological response to a scaled focal cortical impact was compared at 7 days after injury in piglets that were 5 days, 1 month, and 4 months of age at the time of trauma. Despite comparable injury inputs and stable physiological parameters, the percentage of hemisphere injured differed significantly among ages, with the youngest animals sustaining the smallest lesions (0.8%, 8.4%, and 21.5%, for 5-day-, 1-month-, and 4-month-old animals, respectively, p = 0.0018).Conclusions. These results demonstrate that, for this particular focal injury type and severity, vulnerability to mechanical trauma increases progressively during maturation. Because of its developmental and morphological similarity to the human brain, the piglet brain provides distinct advantages in modeling age-specific responses to mechanical trauma. Differences in pathways leading to cell death or repair may be relevant to designing therapies appropriate for patients of different ages.

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“…So, we cannot be entirely sure that Na (29,30). The severity of decreases in Na ϩ ,K ϩ -ATPase activity are dependent on decreases in phosphocreatine as has been measured using 31 P-MRS (8). Also, in the present study, the strong correlation between Na ϩ ,K ϩ -ATPase activity and ECBA suggests that electrical stability of the cortical brain cell membrane is directly related to electrical brain activity.…”

Section: Discussionmentioning

confidence: 54%

“…Inasmuch as the transmembrane enzyme Na ϩ ,K ϩ -ATPase is very susceptible to free radical-related lipid peroxidation (7,8), we investigated in the present study whether DFO prevented free radical-induced alterations of the brain cell membrane after global hypoxia and ischemia, simulating severe birth asphyxia, by measuring cortical cell membrane Na ϩ ,K ϩ -ATPase activity in the early reoxygenation and reperfusion phase in newborn lambs. As Na ϩ ,K ϩ -ATPase is important in maintaining membrane potentials, a second objective of this study was to investigate the relation between cortical cell membrane Na ϩ ,K ϩ -ATPase activity and ECBA in the early reperfusion phase using cerebral function monitoring.…”

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Effects of Deferoxamine, a Chelator of Free Iron, on Na+,K+-ATPase Activity of Cortical Brain Cell Membrane during Early Reperfusion after Hypoxia-Ischemia in Newborn Lambs

et al. 2000

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Free iron chelation after hypoxia-ischemia can reduce free radical-induced damage to brain cell membranes and preserve electrical brain activity. We investigated whether chelation of free iron with deferoxamine (DFO) preserved cortical cell membrane activity of Na ϩ ,K ϩ -ATPase and electrocortical brain activity (ECBA) of newborn lambs during early reperfusion after severe hypoxia-ischemia. Hypoxia was induced in 16 lambs by decreasing the fraction of inspired oxygen to 0.07 for 30 min, followed by a 5-min period of hypotension (mean arterial blood pressure Ͻ35 mm Hg). ECBA (in microvolts) was measured using a cerebral function monitor. Immediately after hypoxia and additional ischemia, eight lambs received DFO (2.5 mg/kg, i.v.), and seven lambs received a placebo (PLAC). Two lambs underwent sham operation. One hundred eighty minutes after completion of hypoxia and ischemia, the brains were obtained and frozen. Na ϩ ,K ϩ -ATPase activity was measured in the P 2 fraction of cortical tissue. Na ϩ ,K ϩ -ATPase activity was 35.1 Ϯ 7.4, 42.0 Ϯ 7.6, and 40.7 Ϯ 1.4 mol inorganic phosphate/mg protein per hour in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p Ͻ 0.05: DFO versus PLAC). ECBA was 11.2 Ϯ 6.1, 14.8 Ϯ 4.8, and 17.5Ϯ.0.5 V in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p ϭ 0.06: DFO versus PLAC). Na Abbreviations DFO, deferoxamine ECBA, electrocortical brain activity PLAC, placebo Q car , carotid blood flow SHAM, sham-operated animals MRS, magnetic resonance spectroscopy P i , inorganic phosphate Hypoxia and ischemia during perinatal asphyxia give rise to an inadequate substrate supply to brain tissue, resulting in damage of neuronal cells. Although recovery of oxygenation and perfusion of the brain is mandatory to prevent further damage, reoxygenation of previously ischemic brain tissue has increasingly been recognized as an important mechanism for additional injury to the neuronal cells and the cerebral microcirculation (1, 2). Production of reactive oxygen species in the early reperfusion phase plays a substantial role in this type of brain cell damage: Reactive oxygen species such as superoxide and hydrogen peroxide can be converted into the highly reactive hydroxyl radical by transition metals, in particular free iron, ultimately leading to lipid peroxidation of the brain cell membrane and cellular damage (3). In recent experimental and clinical studies, we showed that chelation of free iron prevented posthypoxic-ischemic hypoperfusion and metabolic derangements of the brain and preserved ECBA (4, 5). We also found that the free iron chelator DFO effectively lowered free iron in cortical brain tissue (6).Inasmuch as the transmembrane enzyme Na ϩ ,K ϩ -ATPase is very susceptible to free radical-related lipid peroxidation (7, 8), we investigated in the present study whether DFO prevented free radical-induced alterations of the brain cell membrane after global hypoxia and ischemia, simulating severe birth

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Effect of Graded Hypoxia on Brain Cell Membrane Injury in Newborn Piglets

Cited by 64 publications

References 12 publications

Brain Cell Membrane Function during Hypoxia in Hyperglycemic Newborn Piglets

Brain Cell Membrane Function during Hypoxia in Hyperglycemic Newborn Piglets

Maturation-dependent response of the piglet brain to scaled cortical impact

Effects of Deferoxamine, a Chelator of Free Iron, on Na+,K+-ATPase Activity of Cortical Brain Cell Membrane during Early Reperfusion after Hypoxia-Ischemia in Newborn Lambs

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