Nonadditive Neuroprotection With Early Glutamate Receptor Blockade and Delayed Hypothermia After Asphyxia in Preterm Fetal Sheep

George, Sherly; Barrett, Robert D.; Mathai, Sarah; Jensen, Ellen C.; Gunn, Alistair J.

doi:10.1161/strokeaha.112.671982

Cited by 27 publications

(24 citation statements)

References 10 publications

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“…Moreover, we found that delayed hypothermia partially protected the CA3 region but that early treatment with HET0016 did not significantly augment the hypothermic protection. Likewise, early treatment with an N-methyl-D-aspartate receptor antagonist failed to augment neuroprotection afforded by delayed hypothermia in the CA3 region in preterm fetal sheep [41]. HET0016 is capable of partially protecting rodent hippocampal slice cultures from oxygen-glucose deprivation [18].…”

Section: Discussionmentioning

confidence: 99%

Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets

Zhu¹,

Wang²,

Lee³

et al. 2015

Dev Neurosci

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The severity of perinatal hypoxia-ischemia and the delay in initiating therapeutic hypothermia limit the efficacy of hypothermia. After hypoxia-ischemia in neonatal piglets, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been found to contribute to oxidative stress at 3 h of reoxygenation and to eventual neurodegeneration. We tested whether early administration of a 20-HETE synthesis inhibitor after reoxygenation augments neuroprotection with 3-hour delayed hypothermia. In two hypothermic groups, whole body cooling from 38.5 to 34°C was initiated 3 h after hypoxia-ischemia. Rewarming occurred from 20 to 24 h; then anesthesia was discontinued. One hypothermic group received a 20-HETE inhibitor at 5 min after reoxygenation. A sham-operated group and another hypoxia-ischemia group remained normothermic. At 10 days of recovery, resuscitated piglets with delayed hypothermia alone had significantly greater viable neuronal density in the putamen, caudate nucleus, sensorimotor cortex, CA3 hippocampus, and thalamus than did piglets with normothermic recovery, but the values remained less than those in the sham-operated group. In piglets administered the 20-HETE inhibitor before hypothermia, the density of viable neurons in the putamen, cortex and thalamus was significantly greater than in the group with hypothermia alone. Cytochrome P450 4A, which can synthesize 20-HETE, was expressed in piglet neurons in these regions. We conclude that early treatment with a 20-HETE inhibitor enhances the therapeutic benefit of delayed hypothermia in protecting neurons in brain regions known to be particularly vulnerable to hypoxia-ischemia in term newborns.

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Section: Discussionmentioning

confidence: 99%

Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets

Zhu¹,

Wang²,

Lee³

et al. 2015

Dev Neurosci

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“…Although hypoxia-ischemia appears to trigger accumulation of glutamate in the extracellular space, glutamate receptor blockade rendered only partial neuroprotection after severe preterm hypoxia-ischemia (George et al 2012). This is consistent with findings that acute WMI is characterized by a spectrum of necrotic and apoptotic preOL degeneration (Alix et al 2012).…”

Section: Cellular-molecular Mechanisms Of Acute Wmimentioning

confidence: 99%

Pathophysiology of glia in perinatal white matter injury

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Rosenberg

2014

Glia

168

156

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Injury to the preterm brain has a particular predilection for cerebral white matter. White matter injury (WMI) is the most common cause of brain injury in preterm infants and a major cause of chronic neurological morbidity including cerebral palsy. Factors that predispose to WMI include cerebral oxygenation disturbances and maternal-fetal infection. During the acute phase of WMI, pronounced oxidative damage occurs that targets late oligodendrocyte progenitors (preOLs). The developmental predilection for WMI to occur during prematurity appears to be related to both the timing of appearance and regional distribution of susceptible preOLs that are vulnerable to a variety of chemical mediators including reactive oxygen species, glutamate, cytokines, and adenosine. During the chronic phase of WMI, the white matter displays abberant regeneration and repair responses. Early OL progenitors responds to WMI with a rapid robust proliferative response that results in a several fold regeneration of preOLs that fail to terminally differentiate along their normal developmental time course. PreOL maturation arrest appears to be related in part to inhibitory factors that derive from reactive astrocytes in chronic lesions. Recent high field MRI data support that three distinct forms of chronic WMI exist, each of which displays unique MRI and histopathological features. These findings suggest the possibility that therapies directed at myelin regeneration and repair could be initiated early after WMI and monitored over time. These new mechanisms of acute and chronic WMI provide access to a variety of new strategies to prevent or promote repair of WMI in premature infants.

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“…At the end of cooling, fetuses were allowed to rewarm spontaneously. Cooling was induced by circulating cold water (10ºC) through the cooling coil around the fetal body, 2 and was titrated in the first 2 hours to reduce fetal extradural temperature from 39.4 ± 0.1ºC to between 36 and 37ºC. Seven days after occlusion the ewes and fetuses were killed by an overdose of sodium pentobarbitone (9 g, i.v.…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…1 Early electroencephalographic (EEG) monitoring is predictive of long-term outcome after perinatal hypoxia-ischemia at term, 2 but the effect of mild hypothermia on EEG recovery in preterm infants is unknown. In normal humans, mild hypothermia (to ≈33.5°C) is associated with a small reduction in EEG amplitude, with a minor shift in frequencies to theta and beta activity.…”

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confidence: 99%

Hypothermic Neuroprotection Is Associated With Recovery of Spectral Edge Frequency After Asphyxia in Preterm Fetal Sheep

Wassink

Barrett

Davidson

et al. 2015

Stroke

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At 103 to 104 days gestation, fetuses were randomly assigned to sham occlusion followed by normothermia (sham-normothermia, n=8), or whole-body cooling for 72 hours (sham-hypothermia, n=8), or umbilical cord occlusion for 25 minutes, followed by sham hypothermia (occlusion-normothermia, n=12), or whole-body cooling started from 30 minutes (occlusion-early hypothermia, n=10), or 5 hours (occlusion-delayed hypothermia, n=7) after occlusion and continued for 72 hours. Mild whole-body cooling was induced by circulating cold water through the cooling coil. Seven days after occlusion, the ewes and fetuses were killed.Mean arterial pressure, blood gases, EEG activity, and temperature were recorded throughout the experiment. EEG power and spectral Background and Purpose-Electroencephalographic recovery is predictive of outcome after perinatal hypoxia-ischemia, but it is unknown whether early changes in electroencephalographic can predict the response to therapeutic hypothermia in the preterm brain. Methods-0.7 gestation fetal sheep received umbilical cord occlusion or sham occlusion for 25 minutes, followed by sham hypothermia or whole-body cooling started either 30 minutes or 5 hours after occlusion and continued for 72 hours. Results-Early but not delayed hypothermia reduced neuronal loss and microglial induction in the striatum, with faster recovery of spectral edge frequency, reduced seizure burden, and less suppression of electroencephalographic amplitude (P<0.05). Conclusions-Recovery ImmunohistochemistryBrain sections were stained for NeuN (neuronal survival) and IB4 (activated microglia) in the caudate nucleus and putamen, and positive cells were counted stereologically. Statistical AnalysisData were evaluated by repeated measures ANCOVA (SPSS v22, SPSS Inc, IL) and Sidak post hoc analysis. The within subjects' correlation was assessed between EEG amplitude (μV) and extradural temperature. Statistical significance was accepted at P<0.05. Results Blood Composition, Arterial Pressure, and Extradural TemperatureUmbilical cord occlusion was associated with profound hypoxia, mixed metabolic and respiratory acidosis, and hypotension, with rapid recovery after release of occlusion. Hypothermia was associated with a small increase in pH and glucose and a lower PaCO 2 compared with occlusion-normothermia (Table I in the online-only Data Supplement) and no effect on mean arterial pressure (Table II in EEG Power and SEFOcclusion was associated with suppressed EEG power until 84 hours after asphyxia in the occlusion-normothermia group and 72 hours in both hypothermia groups (P<0.05; versus sham-normothermia; Figure 1). Compared with occlusionnormothermia, EEG power was reduced from 1 to 12 hours with early hypothermia, and 6 to 12 hours with delayed hypothermia (P<0.05). Delayed hypothermia was associated with suppressed EEG power compared with early hypothermia from 24 to 30 hours (P<0.05). SEF was significantly suppressed with occlusion-normothermia until 72 hours after occlusion compared with sham-normothermia (P<0.05;...

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Nonadditive Neuroprotection With Early Glutamate Receptor Blockade and Delayed Hypothermia After Asphyxia in Preterm Fetal Sheep

Cited by 27 publications

References 10 publications

Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets

Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets

Pathophysiology of glia in perinatal white matter injury

Hypothermic Neuroprotection Is Associated With Recovery of Spectral Edge Frequency After Asphyxia in Preterm Fetal Sheep

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