Apoptosis in the preterm and near term ovine fetal brain and the effect of intermittent umbilical cord occlusion

Falkowski, Anna L.; Hammond, Rob; Han, V. K. M.; Richardson, Bryan

doi:10.1016/s0165-3806(02)00361-9

Cited by 28 publications

(36 citation statements)

References 33 publications

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“…In agreement with previous studies (Falkowski et al, 2002), programmed cell death was very low throughout the control cerebral white matter. When detected, these rare TUNELlabeled nuclei typically double labeled with the O1 monoclonal antibody but not with antibodies against GFAP, vimentin, or isolectin B4.…”

Section: Differential Vulnerability Of Glia In Severe White Matter Lesupporting

confidence: 93%

Spatial Heterogeneity in Oligodendrocyte Lineage Maturation and Not Cerebral Blood Flow Predicts Fetal Ovine Periventricular White Matter Injury

Riddle¹,

Luo²,

Manese³

et al. 2006

J. Neurosci.

167

223

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Although periventricular white matter injury (PWMI) is the leading cause of chronic neurological disability and cerebral palsy in survivors of premature birth, the cellular-molecular mechanisms by which ischemia-reperfusion contributes to the pathogenesis of PWMI are not well defined. To define pathophysiologic relationships among ischemia, acute cerebral white matter damage, and vulnerable target populations, we used a global cerebral ischemia-reperfusion model in the instrumented 0.65 gestation fetal sheep. We developed a novel method to make repeated measurements of cerebral blood flow using fluorescently labeled microspheres to resolve the spatial heterogeneity of flow in situ in three-dimensional space. Basal flow in the periventricular white matter (PVWM) was significantly lower than in the cerebral cortex. During global cerebral ischemia induced by carotid occlusion, flow to all regions was reduced by nearly 90%. Ischemia of 30 or 37 min duration generated selective graded injury to frontal and parietal PVWM, two regions of predilection for human PWMI. Injury was proportional to the duration of ischemia and increased markedly with 45 min of ischemia to extensively damage cortical and subcortical gray matter. Surprisingly, the distribution of PVWM damage was not uniform and not explained by heterogeneity in the degree of white matter ischemia. Rather, the extent of white matter damage coincided with the presence of a susceptible population of late oligodendrocyte progenitors. These data support that although ischemia is necessary to generate PWMI, the presence of susceptible populations of oligodendrocyte progenitors underlies regional predilection to injury.

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Section: Differential Vulnerability Of Glia In Severe White Matter Lesupporting

confidence: 93%

Spatial Heterogeneity in Oligodendrocyte Lineage Maturation and Not Cerebral Blood Flow Predicts Fetal Ovine Periventricular White Matter Injury

Riddle¹,

Luo²,

Manese³

et al. 2006

J. Neurosci.

167

223

View full text Add to dashboard Cite

show abstract

“…In contrast to animals that sustained hypoxia-ischemia, control animals had rare TUNEL-labeled cells in the regions shown in Figure 6. This finding was consistent with very similar data from the ovine fetal brain (Falkowski et al, 2002), which supports the concept that programmed cell death is quite low at this window in development. Figure 7A shows the typical distribution of TUNEL-labeled nuclei in the cortical plate.…”

Section: Hypoxia-ischemia At E22 Generates Distinct Patterns Of Acutesupporting

confidence: 91%

Preterm Fetal Hypoxia-Ischemia Causes Hypertonia and Motor Deficits in the Neonatal Rabbit: A Model for Human Cerebral Palsy?

Derrick¹,

Luo²,

Bregman³

et al. 2004

J. Neurosci.

198

265

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Prenatal hypoxia-ischemia to the developing brain has been strongly implicated in the subsequent development of the hypertonic motor deficits of cerebral palsy (CP) in premature and full-term infants who present with neonatal encephalopathy. Despite the enormous impact of CP, there is no animal model that reproduces the hypertonia and motor disturbances of this disorder. We report a rabbit model of in utero placental insufficiency, in which hypertonia is accompanied by marked abnormalities in motor control. Preterm fetuses (67-70% gestation) were subjected to sustained global hypoxia. The dams survived and gave spontaneous birth. At postnatal day 1, the pups that survived were subjected to a battery of neurobehavioral tests developed specifically for these animals, and the tests were videotaped and scored in a masked manner. Newborn pups of hypoxic groups displayed significant impairment in multiple tests of spontaneous locomotion, reflex motor activity, and the coordination of suck and swallow. Increased tone of the limbs at rest and with active flexion and extension were observed in the survivors of the preterm insult.Histopathological studies identified a distinct pattern of acute injury to subcortical motor pathways that involved the basal ganglia and thalamus. Persistent injury to the caudate putamen and thalamus at P1 was significantly correlated with hypertonic motor deficits in the hypoxic group. Antenatal hypoxia-ischemia at preterm gestation results in hypertonia and abnormalities in motor control. These findings provide a unique behavioral model to define mechanisms and sequelae of perinatal brain injury from antenatal hypoxia-ischemia.

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“…Chronic instrumentation also allows a wide range of practical and clinically pertinent cerebral insults to be administered. These include global cephalic ischemia [65], systemic hypotension or hypoxemia [66][67][68], single or repeated cord occlusion [69][70][71], increased intracranial pressure [72], and administration of infectious agents or exogenous inflammatory mediators [73][74][75]. These insults can be graded in intensity and duration to mimic the human situation.…”

Section: Advantages and Disadvantages Of The Fetal Sheep To Model Wmimentioning

confidence: 99%

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

et al. 2012

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Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. The developing brain is particularly susceptible to cerebral white matter injury related to hypoxia-ischemia. Cerebral white matter development in fetal sheep shares many anatomical and physiological similarities with humans. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and have provided access to complex clinically relevant studies of cerebral blood flow and neuroimaging that are not feasible in smaller laboratory animals. Here, we focus on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to white matter injury. Recent advances include spatially defined measurements of cerebral blood flow in utero, the definition of cellular maturational factors that define the topography of injury and the application of high-field magnetic resonance imaging to define novel neuroimaging signatures for specific types of chronic white matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

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Apoptosis in the preterm and near term ovine fetal brain and the effect of intermittent umbilical cord occlusion

Cited by 28 publications

References 33 publications

Spatial Heterogeneity in Oligodendrocyte Lineage Maturation and Not Cerebral Blood Flow Predicts Fetal Ovine Periventricular White Matter Injury

Spatial Heterogeneity in Oligodendrocyte Lineage Maturation and Not Cerebral Blood Flow Predicts Fetal Ovine Periventricular White Matter Injury

Preterm Fetal Hypoxia-Ischemia Causes Hypertonia and Motor Deficits in the Neonatal Rabbit: A Model for Human Cerebral Palsy?

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

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