Effect of cerebral hypothermia and asphyxia on the subventricular zone and white matter tracts in preterm fetal sheep

Barrett, Robert D.; Naylor, Andrew S.; George, Sherly; Dean, Justin M.; Gunn, Alistair J.

doi:10.1016/j.brainres.2012.06.018

Cited by 25 publications

(27 citation statements)

References 32 publications

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“…Given that the Olig2 labeled cells include all immature/mature oligodendrocytes [22], these data are consistent with the hypothesis that the reduction in immature/mature oligodendrocytes corresponds with increased numbers of preoligodendrocytes. We have previously shown that in the same model as the present study, there is significant loss of oligodendrocyte progenitor cells three days after asphyxia [33], [36] and we now show that after 7 days there was a significant increase in proliferation in the occlusion-vehicle group compared to sham control. The exuberant proliferation response to injury is almost entirely mediated by oligodendrocyte progenitor cells [37], as shown here by co-localization of Olig2 and Ki-67.…”

Section: Discussionsupporting

confidence: 83%

“…The exuberant proliferation response to injury is almost entirely mediated by oligodendrocyte progenitor cells [37], as shown here by co-localization of Olig2 and Ki-67. Taken as a whole, these data suggest early loss of preoligodendrocytes [36] followed by significant proliferation of new preoligodendrocytes with either impaired maturation, or at least failure to replace immature/mature oligodendrocytes by day 7. This is consistent with data in the neonatal rat and the preterm fetal sheep that showed degeneration of preoligodendrocytes offset by dramatic proliferation, but impaired maturation after hypoxia ischemia [27], [28] and with the critical finding of maturational arrest of preoligodendrocytes in human neonatal white matter injury at post-mortem [2].…”

Section: Discussionmentioning

confidence: 77%

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Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

et al. 2014

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Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 77%

Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

et al. 2014

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“…We have previously shown that after 3 days recovery at this gestation, occlusion was associated with loss of O4 immunostaining, a marker of immature oligodendrocytes but sparing of CNPase-positive cells. 24,25 Further, in the present study, we found a substantial increase in proliferation, with co-localization of Ki-67 with Olig-2-positive cells, and critically, with PDGFR-a positive oligodendrocyte progenitors. This combination of findings suggests that rather than a primary loss of mature oligodendrocytes, asphyxia was associated with initial loss of immature oligodendroglia, followed by intense restorative proliferation of oligodendrocyte progenitors that restored total number of cells, but with impaired lineage maturation.…”

Section: Discussionsupporting

confidence: 74%

“…These differences were not associated with any differences in the fetal brain temperature between groups. 24 Prolonged umbilical cord occlusion was associated with substantial fetal subcortical injury to white and gray matter. Intriguingly, there was no significant net loss of Olig-2-positive oligodendrocytes in the intragyral and periventricular white matter after 7 days recovery.…”

Section: Discussionmentioning

confidence: 99%

Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

Drury

Davidson

Bennet

et al. 2013

J Cereb Blood Flow Metab

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Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n ¼ 8), or the equivalent volume of vehicle (2% ethanol, n ¼ 7), or saline (n ¼ 8), or maternal saline plus sham occlusion (n ¼ 8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippocampus, with reduced proliferation and increased ameboid microglia in the white matter (Po0.05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter (Po0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin. Keywords: asphyxia; brain; ethanol; melatonin; neuroprotection; preterm fetus INTRODUCTION Birth asphyxia is relatively common with preterm birth, and remains a significant cause of neonatal death and neurodevelopmental delay. 1 Excess free radical production during asphyxia and early reperfusion are associated with lipid peroxidation, nucleic acid damage, and mitochondrial dysfunction that promote cell death. 2 Melatonin is a naturally occurring indolamine involved in circadian rhythm, which also has antioxidant properties. 3,4 It readily crosses the human and ovine placentae making it an attractive option for prophylactic treatment of fetuses at high risk of perinatal hypoxia. 4 Melatonin given before and immediately after hypoxia-ischemia is neuroprotective in postnatal rodents. [5][6][7][8][9] Postnatally, high-dose (5 mg/kg per hour over 6 hours) melatonin given immediately after hypoxia-ischemia in term piglets augmented protection from therapeutic hypothermia on both magnetic resonance spectroscopy markers of anaerobic stress, and histopathology. 10 In contrast, there have been few studies of antenatal treatment and relatively limited large-animal evidence that prophylactic lowdose melatonin can protect against hypoxic-ischemic injury in the preterm fetus. In fetal sheep, Miller et al 11 showed that maternal prophylactic melatonin (1 mg total) given before 10-minute umbilical cord occlusion at term-equivalent was associated with reduced brain lipid peroxidation, neuronal death, microglial activation, and astrogliosis. 11,12 In preterm fetal sheep at 0.6 gestation (Term ¼ 147 days) fetal infusion of high-dose (20 mg/kg) J...

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“…A study of a preterm sheep model of HI showed that oligodendrocyte precursor cell proliferation in the periventricular white matter is unaffected by hypothermia [19], whereas in a rat model in the corpus callosum hypothermia was shown to enhance oligodendrocyte precursor cell proliferation and maturation. Interestingly, in the fetal sheep HI model, hypothermia did not increase or decrease expression of Ki-67, a nonspecific marker for proliferation, in the SVZ, where cells with potential for both neuronal and glial fates are actively dividing [20]. In the absence of injury hypothermia can actually suppresses NSPC proliferation in the hippocampus [21], suggesting that there is the potential for an adverse effect of this therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

Effects of Neonatal Hypoxic-Ischemic Injury and Hypothermic Neuroprotection on Neural Progenitor Cells in the Mouse Hippocampus

Kwak¹,

Lim²,

Kang

et al. 2015

Dev Neurosci

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Neonatal hypoxic-ischemic injury (HI) results in widespread cerebral encephalopathy and affects structures that are essential for neurocognitive function, such as the hippocampus. The dentate gyrus contains a reservoir of neural stem and progenitor cells (NSPCs) that are critical for postnatal development and normal adult function of the hippocampus, and may also facilitate the recovery of function after injury. Using a neonatal mouse model of mild-to-moderate HI and immunohistochemical analysis of NSPC development markers, we asked whether these cells are vulnerable to HI and how they respond to both injury and hypothermic therapy. We found that cleaved caspase-3 labeling in the subgranular zone, where NSPCs are located, is increased by more than 30-fold after HI. The population of cells positive for both proliferating cell nuclear antigen and nestin (PCNA+Nes+), which represent primarily actively proliferating NSPCs, are acutely decreased by 68% after HI. The NSPC population expressing NeuroD1, a marker for NSPCs transitioning to become fate-committed neural progenitors, was decreased by 47%. One week after HI, there was a decrease in neuroblasts and immature neurons in the dentate gyrus, as measured by doublecortin (DCX) immunolabeling, and at the same time PCNA+Nes+ cell density was increased by 71%. NSPCs expressing Tbr2, which identifies a highly proliferative intermediate neural progenitor population, increased by 107%. Hypothermia treatment after HI partially rescues both the acute decrease in PCNA+Nes+ cell density at 1 day after injury and the chronic loss of DCX immunoreactivity and reduction in NeuroD1 cell density measured at 1 week after injury. Thus, we conclude that HI causes an acute loss of dentate gyrus NSPCs, and that hypothermia partially protects NSPCs from HI.

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Effect of cerebral hypothermia and asphyxia on the subventricular zone and white matter tracts in preterm fetal sheep

Cited by 25 publications

References 32 publications

Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

Effects of Neonatal Hypoxic-Ischemic Injury and Hypothermic Neuroprotection on Neural Progenitor Cells in the Mouse Hippocampus

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