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

2016 ◽  
Vol 37 (4) ◽  
pp. 1362-1373 ◽  
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.

The Effect of Antenatal Betamethasone on White Matter Inflammation and Injury in Fetal Sheep and Ventilated Preterm Lambs

2018 ◽  
Vol 40 (5-6) ◽  
pp. 497-507 ◽  
Author(s):  
Vanesa Stojanovska ◽  
Samantha K. Barton ◽  
Mary Tolcos ◽  
Andrew W. Gill ◽  
Martin Kluckow ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
White Matter ◽  
Oxygen Delivery ◽  
Late Preterm ◽  
Limited Information ◽  
Fetal Sheep ◽  
Activated Microglia ◽  
Protein Extravasation ◽  
To Receive ◽  
And Oxidative Stress

Antenatal administration of betamethasone (BM) is a common antecedent of preterm birth, but there is limited information about its impact on the acute evolution of preterm neonatal brain injury. We aimed to compare the effects of maternal BM in combination with mechanical ventilation on the white matter (WM) of late preterm sheep. At 0.85 of gestation, pregnant ewes were randomly assigned to receive intra-muscular (i.m.) saline (n = 9) or i.m. BM (n = 13). Lambs were delivered and unventilated controls (UVCSal, n = 4; UVCBM, n = 6) were humanely killed without intervention; ventilated lambs (VentSal, n = 5; VentBM, n = 7) were injuriously ventilated for 15 min, followed by conventional ventilation for 75 min. Cardiovascular and cerebral haemodynamics and oxygenation were measured continuously. The cerebral WM underwent assessment of inflammation and injury, and oxidative stress was measured in the cerebrospinal fluid (CSF). In the periventricular and subcortical WM tracts, the proportion of amoeboid (activated) microglia, the density of astrocytes, and the number of blood vessels with protein extravasation were higher in UVCBM than in UVCSal (p < 0.05 for all). During ventilation, tidal volume, mean arterial pressure, carotid blood flow, and oxygen delivery were higher in ­VentBM lambs (p < 0.05 vs. VentSal). In the subcortical WM, microglial infiltration was increased in the VentSal group compared to UVCSal. The proportion of activated microglia and protein extravasation was higher in the VentBM group compared to VentSal within the periventricular and subcortical WM tracts (p < 0.05). CSF oxidative stress was increased in the VentBM group compared to UVCSal, UVCBM, and VentSal groups (p < 0.05). Antenatal BM was associated with inflammation and vascular permeability in the WM of late preterm fetal sheep. During the immediate neonatal period, the increased carotid perfusion and oxygen delivery in BM-treated lambs was associated with increased oxidative stress, microglial activation and microvascular injury.

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

2007 ◽  
Vol 28 (5) ◽  
pp. 995-1008 ◽  
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.

Subclinical exposure to low-dose endotoxin impairs EEG maturation in preterm fetal sheep

2012 ◽  
Vol 303 (3) ◽  
pp. R270-R278 ◽  
Author(s):  
Michael J. Keogh ◽  
Laura Bennet ◽  
Paul P. Drury ◽  
Lindsea C. Booth ◽  
Sam Mathai ◽  
...  
Keyword(s):  
White Matter ◽  
Plasma Cortisol ◽  
Low Dose ◽  
Blood Gases ◽  
Power Spectral Analysis ◽  
Periventricular White Matter ◽  
Fetal Sheep ◽  
Beta Power ◽  
Dose Infusion ◽  
Arterial Plasma

Exposure to chorioamnionitis is strongly associated with neurodevelopmental disability after premature birth; however, it remains unclear whether subclinical infection affects functional EEG maturation. Chronically instrumented 103–104-day-old (0.7 gestational age: term 147 days) fetal sheep in utero were randomized to receive either gram-negative LPS by continuous low-dose infusion (100 ng iv over 24 h, followed by 250 ng/24 h for 4 days; n = 6) or the same volume of normal saline ( n = 9). Arterial plasma cortisol, ACTH, and IL-6 were measured. The delta (0–3.9 Hz), theta (4–7.9 Hz), alpha (8–12.9 Hz), and beta (13–22 Hz) components of the EEG were determined by power spectral analysis. Brains were taken after 10 days for histopathology. There were no changes in blood gases, cardiovascular variables, or EEG power during LPS infusion, but a transient rise in plasma cortisol and IL-6 ( P < 0.05). LPS infusion was associated with loss of the maturational increase to higher frequency activity, with reduced alpha and beta power, and greater delta power than saline controls from 6 to 10 days ( P < 0.05). Histologically, LPS was associated with increased numbers of microglia and TNF-α-positive cells in the periventricular white matter and frontoparietal cortex, increased caspase-3-positive cells in white matter, but no loss of CNPase-positive oligodendrocytes, Nurr-1 subplate cells, or gyral complexity. These data suggest that low-dose endotoxin exposure can impair EEG maturation in preterm fetal sheep in association with neural inflammation but without hemodynamic disturbances or cortical injury.

scholarly journals Interleukin-1 blockade attenuates white matter inflammation and oligodendrocyte loss after progressive systemic lipopolysaccharide exposure in near-term fetal sheep

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Sharmony B. Kelly ◽  
Vanesa Stojanovska ◽  
Valerie A. Zahra ◽  
Alison Moxham ◽  
Suzanne L. Miller ◽  
...  
Keyword(s):  
White Matter ◽  
Carotid Artery ◽  
Caspase 3 ◽  
Brain Inflammation ◽  
Brain Maturation ◽  
Fetal Sheep ◽  
Eeg Activity ◽  
Near Term ◽  
Artery Perfusion ◽  
Circulating Cytokines

Abstract Background Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). Methods Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n = 9). Sheep were euthanized 4 days after starting infusions for histology. Results LPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P < 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival. Conclusion IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.

scholarly journals Human Amnion Epithelial Cells Protect against White Matter Brain Injury after Repeated Endotoxin Exposure in the Preterm Ovine Fetus

2017 ◽  
Vol 26 (4) ◽  
pp. 541-553 ◽  
Author(s):  
Tamara Yawno ◽  
Tharani Sabaretnam ◽  
Jingang Li ◽  
Courtney Mcdonald ◽  
Rebecca Lim ◽  
...  
Keyword(s):  
Brain Injury ◽  
White Matter ◽  
Epithelial Cells ◽  
Fetal Brain ◽  
Brain Inflammation ◽  
Periventricular White Matter ◽  
Fetal Sheep ◽  
Human Amnion ◽  
Activated Microglia ◽  
Amnion Epithelial Cells

Intrauterine inflammation is a significant cause of injury to the developing fetal brain. Using a preterm fetal sheep model of in utero infection, we asked whether human amnion epithelial cells (hAECs) were able to reduce inflammation-induced fetal brain injury. Surgery was undertaken on pregnant sheep at ~105 days gestation (term is 147 days) for implantation of vascular catheters. Lipopolysaccharide (LPS; 150 ng/kg bolus) or saline was administered IV at 109, 110, and 111 days. Sixty million fluorescent-labeled hAECs were administered at 110, 111, and 112 days gestation via the brachial artery catheter. Brains were collected at 114 days for histological assessment. hAECs were observed within the cortex, white matter, and hippocampus. Compared to control lambs, LPS administration was associated with significant and widespread fetal brain inflammation and injury as evidenced by increased number of activated microglia in the periventricular white matter ( p = 0.02), increased pyknosis, cell degeneration ( p = 0.01), and a nonsignificant trend of fewer oligodendrocytes in the subcortical and periventricular white matter. Administration of hAECs to LPS-treated animals was associated with a significant mitigation in both inflammation and injury as evidenced by fewer activated microglia ( p = 0.03) and pyknotic cells ( p = 0.03), significantly more oligodendrocytes in the subcortical and periventricular white matter ( p = 0.01 and 0.02, respectively), and more myelin basic protein-positive cells within the periventricular white matter ( p = 0.02). hAEC administration to fetal sheep exposed to multiple doses of LPS dampens the resultant fetal inflammatory response and mitigates associated brain injury.

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

2009 ◽  
Vol 16 (8) ◽  
pp. 758-766 ◽  
Author(s):  
Yves Garnier ◽  
Alessandro Frigiola ◽  
Giovanni Li Volti ◽  
Pasquale Florio ◽  
Rosanna Frulio ◽  
...  
Keyword(s):  
White Matter ◽  
White Matter Injury ◽  
Periventricular White Matter ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Endotoxin Administration

Extracellular amino acids and lipid peroxidation products in periventricular white matter during and after cerebral ischemia in preterm fetal sheep

2008 ◽  
Vol 105 (6) ◽  
pp. 2214-2223 ◽  
Author(s):  
Mhoyra Fraser ◽  
Laura Bennet ◽  
Pierre L. Van Zijl ◽  
Tessa J. Mocatta ◽  
Christopher E. Williams ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lipid Peroxidation ◽  
White Matter ◽  
Cerebral Ischemia ◽  
Periventricular White Matter ◽  
Fetal Sheep ◽  
Lipid Peroxidation Products

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

2013 ◽  
Vol 34 (1) ◽  
pp. 126-135 ◽  
Author(s):  
Paul P Drury ◽  
Joanne O Davidson ◽  
Laura Bennet ◽  
Lindsea C Booth ◽  
Sidhartha Tan ◽  
...  
Keyword(s):  
White Matter ◽  
Microglial Activation ◽  
Low Dose ◽  
Neuronal Survival ◽  
Antioxidant Properties ◽  
Neuronal Loss ◽  
Limited Information ◽  
Melatonin Treatment ◽  
Fetal Sheep ◽  
Naturally Occurring

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=8), or the equivalent volume of vehicle (2% ethanol, n=7), or saline ( n=8), or maternal saline plus sham occlusion ( n=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 ( P<0.05). 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 ( P<0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin.

scholarly journals Magnetic Resonance Imaging Correlates of White Matter Gliosis and Injury in Preterm Fetal Sheep Exposed to Progressive Systemic Inflammation

2020 ◽  
Vol 21 (23) ◽  
pp. 8891
Author(s):  
Robert Galinsky ◽  
Yohan van de Looij ◽  
Natasha Mitchell ◽  
Justin M. Dean ◽  
Simerdeep K. Dhillon ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
White Matter ◽  
Magnetic Resonance ◽  
High Field ◽  
Diffusion Tensor ◽  
Periventricular White Matter ◽  
Diffusion Tensor Mri ◽  
Resonance Imaging ◽  
Fetal Sheep ◽  
Field Diffusion

Progressive fetal infection/inflammation is strongly associated with neural injury after preterm birth. We aimed to test the hypotheses that progressively developing fetal inflammation leads to neuroinflammation and impaired white matter development and that the histopathological changes can be detected using high-field diffusion tensor magnetic resonance imaging (MRI). Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive intravenous saline (control; n = 6) or a progressive infusion of lipopolysaccharide (LPS, 200 ng intravenous over 24 h then doubled every 24 h for 5 days to induce fetal inflammation, n = 7). Sheep were killed 10 days after starting the infusions, for histology and high-field diffusion tensor MRI. Progressive LPS infusion was associated with increased circulating interleukin (IL)-6 concentrations and moderate increases in carotid artery perfusion and the frequency of electroencephalogram (EEG) activity (p < 0.05 vs. control). In the periventricular white matter, fractional anisotropy (FA) was increased, and orientation dispersion index (ODI) was reduced (p < 0.05 vs. control for both). Histologically, in the same brain region, LPS infusion increased microglial activation and astrocyte numbers and reduced the total number of oligodendrocytes with no change in myelination or numbers of immature/mature oligodendrocytes. Numbers of astrocytes in the periventricular white matter were correlated with increased FA and reduced ODI signal intensities. Astrocyte coherence was associated with increased FA. Moderate astrogliosis, but not loss of total oligodendrocytes, after progressive fetal inflammation can be detected with high-field diffusion tensor MRI.

Acute on chronic exposure to endotoxin in preterm fetal sheep

2013 ◽  
Vol 304 (3) ◽  
pp. R189-R197 ◽  
Author(s):  
Sam Mathai ◽  
Lindsea C. Booth ◽  
Joanne O. Davidson ◽  
Paul P. Drury ◽  
Mhoyra Fraser ◽  
...  
Keyword(s):  
White Matter ◽  
Low Dose ◽  
White Matter Lesions ◽  
White Matter Injury ◽  
Fetal Mortality ◽  
High Dose ◽  
Periventricular White Matter ◽  
Fetal Sheep ◽  
Severe Hypotension ◽  
Dose Infusion

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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