Increased Maternal/Fetal Blood S100B Levels Following Systemic Endotoxin Administration and Periventricular White Matter Injury in Preterm Fetal Sheep

Acute, high-dose exposure to endotoxin lipopolysaccharide (LPS) in preterm fetal sheep can trigger periventricular white matter lesions (PVL), in association with severe hypotension/hypoxemia and significant mortality. Intriguingly, however, chronic or repeated exposure to LPS can induce tachyphylaxis. We therefore tested the hypothesis that progressive, acute on chronic fetal infection would be associated with white matter injury with little fetal mortality. Chronically instrumented preterm (0.7 gestational age) fetal sheep were exposed to a continuous low-dose LPS infusion (100 ng over 24 h, followed by 250 ng/24 h for 96 h) or saline. Boluses of 1 μg LPS or saline were given at 48, 72, and 96 h; sheep were killed at day 10. Six of 11 fetal sheep exposed to saline infusion + LPS boluses died 4–7 h after the first bolus. In contrast, there was no fetal mortality after saline infusions alone ( n = 9), low-dose LPS infusion + saline boluses ( n = 5), or low-dose LPS + LPS boluses ( n = 9). Low-dose LPS infusion + LPS boluses was associated with greater microglial induction than low-dose LPS + saline boluses but a similar area of periventricular white matter inflammation. One fetus developed severe focal white matter necrosis after LPS infusion + boluses. The acute cardiovascular compromise associated with high-dose, acute exposure to LPS is markedly attenuated by previous low-dose infusions, with limited apparent exacerbation of periventricular white matter injury compared with low-dose infusion alone.

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Topical Review: Role of Instrumented Fetal Sheep Preparations in Defining the Pathogenesis of Human Periventricular White-Matter Injury

Journal of Child Neurology ◽

10.1177/08830738060210070101 ◽

2006 ◽

Vol 21 (7) ◽

pp. 582-589 ◽

Cited By ~ 80

Author(s):

Stephen A. Back ◽

Art Riddle ◽

A. Roger Hohimer

Keyword(s):

White Matter ◽

White Matter Injury ◽

Periventricular White Matter ◽

Fetal Sheep ◽

Topical Review

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Maturational Effects of Lipopolysaccharide on White-Matter Injury in Fetal Sheep

Journal of Child Neurology ◽

10.1177/08830738050200120501 ◽

2005 ◽

Vol 20 (12) ◽

pp. 960-964 ◽

Cited By ~ 36

Author(s):

Pernilla Svedin ◽

Ingmar Kjellmer ◽

Anna-Karin Welin ◽

Sofia Blad ◽

Carina Mallard

Keyword(s):

White Matter ◽

White Matter Injury ◽

Fetal Sheep

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Window of Opportunity of Cerebral Hypothermia for Postischemic White Matter Injury in the Near-Term Fetal Sheep

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000123904.17746.92 ◽

2004 ◽

Vol 24 (8) ◽

pp. 877-886 ◽

Cited By ~ 80

Author(s):

Vincent Roelfsema ◽

Laura Bennet ◽

Sherly George ◽

David Wu ◽

Jian Guan ◽

...

Keyword(s):

White Matter ◽

Cerebral Ischemia ◽

Caspase 3 ◽

Basic Protein ◽

White Matter Injury ◽

Window Of Opportunity ◽

Reactive Microglia ◽

Fetal Sheep ◽

Near Term ◽

Protein Density

Postresuscitation cerebral hypothermia is consistently neuroprotective in experimental preparations; however, its effects on white matter injury are poorly understood. Using a model of reversible cerebral ischemia in unanesthetized near-term fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.4±0.1°C to between 30 and 33°C), induced at different times after reperfusion and continued for 72 hours after ischemia, on injury in the parasagittal white matter 5 days after ischemia. Cooling started within 90 minutes of reperfusion was associated with a significant increase in bioactive oligodendrocytes in the intragyral white matter compared with sham cooling (41±20 vs 18±11 per field, P < 0.05), increased myelin basic protein density and reduced expression of activated caspase-3 (14±12 vs 91±51, P < 0.05). Reactive microglia were profoundly suppressed compared with sham cooling (4±6 vs 38±18 per field, P < 0.05) with no effect on numbers of astrocytes. When cooling was delayed until 5.5 hours after reperfusion there was no significant effect on loss of oligodendrocytes (24±12 per field). In conclusion, hypothermia can effectively protect white matter after ischemia, but only if initiated early after the insult. Protection was closely associated with reduced expression of both activated caspase-3 and of reactive microglia.

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Cerebral Blood Flow Heterogeneity in Preterm Sheep: Lack of Physiologic Support for Vascular Boundary Zones in Fetal Cerebral White Matter

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600597 ◽

2007 ◽

Vol 28 (5) ◽

pp. 995-1008 ◽

Cited By ~ 44

Author(s):

Melissa M McClure ◽

Art Riddle ◽

Mario Manese ◽

Ning Ling Luo ◽

Dawn A Rorvik ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Ischemia Reperfusion ◽

Three Dimensional ◽

Cerebral White Matter ◽

Periventricular White Matter ◽

Fetal Sheep ◽

Border Zones ◽

Neurologic Disability

Periventricular white matter (PVWM) injury is the leading cause of neurologic disability in survivors of prematurity. To address the role of ischemia in PVWM and cerebral cortical injury, we hypothesized that immaturity of spatially distal vascular ‘end zones’ or ‘border zones’ predisposes PVWM to greater decreases in cerebral blood flow (CBF) than more proximal structures. We quantified regional CBF with fluorescently labeled microspheres in 0.65 gestation fetal sheep in histopathologically defined three-dimensional regions by post hoc digital dissection and coregistration algorithms. Basal flow in PVWM was significantly lower than in gyral white matter and cortex, but was equivalent in superficial, middle, and deep PVWM. Absolute and relative CBF (expressed as percentage of basal) did not differ significantly during ischemia or reperfusion between PVWM, gyral white matter, or cortex. Moreover, CBF during ischemia-reperfusion was equivalent in three adjacent PVWM levels and was not consistent with the magnitude of severity of PVWM injury, defined by TUNEL (terminal deoxynucleotidyltransferase-mediated dUPT nick end labeling) staining. However, the magnitude of ischemia was predicted by the severity of discrete cortical lesions. Hence, unlike cerebral cortex, unique CBF disturbances did not account for the distribution of PVWM injury. Previously defined cellular maturational factors, thus, appear to have a greater influence on PVWM vulnerability to ischemic injury than the presence of immature vascular boundary zones.

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164: Glial fibrillary acidic protein as a serum biomarker for the early identification of neonatal periventricular white matter injury in preterm neonates

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2011.10.182 ◽

2012 ◽

Vol 206 (1) ◽

pp. S86

Author(s):

Amanda Stewart ◽

Jacky Jennings ◽

Aylin Tekes ◽

Huisman Thierry ◽

Frances Northington ◽

...

Keyword(s):

White Matter ◽

Glial Fibrillary Acidic Protein ◽

Early Identification ◽

Acidic Protein ◽

White Matter Injury ◽

Serum Biomarker ◽

Preterm Neonates ◽

Periventricular White Matter

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Magnesium sulfate reduces EEG activity but is not neuroprotective after asphyxia in preterm fetal sheep

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16655548 ◽

2016 ◽

Vol 37 (4) ◽

pp. 1362-1373 ◽

Cited By ~ 19

Author(s):

Robert Galinsky ◽

Vittoria Draghi ◽

Guido Wassink ◽

Joanne O Davidson ◽

Paul P Drury ◽

...

Keyword(s):

White Matter ◽

Magnesium Sulfate ◽

Marked Reduction ◽

Neuronal Loss ◽

Periventricular White Matter ◽

Fetal Sheep ◽

Eeg Activity ◽

Fetal Movements ◽

To Receive ◽

Anticonvulsant Effects

Magnesium sulfate is now widely recommended for neuroprotection for preterm birth; however, this has been controversial because there is little evidence that magnesium sulfate is neuroprotective. Preterm fetal sheep (104 days gestation; term is 147 days) were randomly assigned to receive sham occlusion (n = 7), i.v. magnesium sulfate (n = 10) or saline (n = 8) starting 24 h before asphyxia until 24 h after asphyxia. Sheep were killed 72 h after asphyxia. Magnesium sulfate infusion reduced electroencephalograph power and fetal movements before asphyxia. Magnesium sulfate infusion did not affect electroencephalograph power during recovery, but was associated with marked reduction of the post-asphyxial seizure burden (mean ± SD: 34 ± 18 min vs. 107 ± 74 min, P < 0.05). Magnesium sulfate infusion did not affect subcortical neuronal loss. In the intragyral and periventricular white matter, magnesium sulfate was associated with reduced numbers of all (Olig−2+ve) oligodendrocytes in the intragyral (125 ± 23 vs. 163 ± 38 cells/field) and periventricular white matter (162 ± 39 vs. 209 ± 44 cells/field) compared to saline-treated controls ( P < 0.05), but no effect on microglial induction or astrogliosis. In conclusion, a clinically comparable dose of magnesium sulfate showed significant anticonvulsant effects after asphyxia in preterm fetal sheep, but did not reduce asphyxia-induced brain injury and exacerbated loss of oligodendrocytes.

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