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.

Abstract WP112: Residual Damage is Reduced Following Human Umbilical Tissue Derived Cell Infusion in a Non-human Primate Model of Cortical Injury

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Mary E Orczykowski ◽  
Eli Shobin ◽  
Samantha M Calderazzo ◽  
Brian C Kramer ◽  
Farzad Mortazavi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
White Matter ◽  
Motor Cortex ◽  
Oxidative Damage ◽  
Primary Motor Cortex ◽  
Primate Model ◽  
Cortical Injury ◽  
Activated Microglia ◽  
And Oxidative Stress ◽  
Human Primate

Introduction: Stroke is the leading cause of long-term disability in the United States due to impairments that endure after brain injury. While studies in rodent models have evaluated numerous neurorestorative treatments following stroke, none have received FDA approval. We evaluated a therapy using human umbilical tissue-derived cells (hUTC) as a potential neurorestorative treatment in our non-human primate model of cortical injury limited to the hand area of primary motor cortex. Given treatment 24 hours after injury, hUTC treated monkeys showed a significantly greater degree of recovery of fine motor function compared to vehicle treated controls (Moore et al., 2013). To explore the effect of hUTC, histopathological markers of inflammation and oxidative stress were assessed. Hypothesis: Treatment with hUTC will enhance the recruitment of glia to the injury and reduce the cascade of inflammation and oxidative stress. Methods: Using immunohistochemistry, activated microglia (LN3), reactive astrocytes (GFAP), oxidative damage (4HNE), and accumulated hemosiderin (Perls’ Prussian Blue) were quantified in ipsilesional primary motor cortex and underlying white matter. Microglia were counted using unbiased stereology. A Sholl Analysis was performed on traced perilesional astrocytes. The area of oxidative damage and hemosiderin was assessed using densitometry. Results: Compared to vehicle controls, density of activated microglia in the hUTC treated group approached a significant increase in the perilesional gray and white matter (p=0.070; p=0.092). Astrocytes exhibited more complex processes in treated monkeys (p=0.042). Staining for 4HNE was significantly reduced in white matter underlying the lesion in treated monkeys (p=0.033). Lastly, both the area and intensity of Perls’ staining for hemosiderin was significantly reduced in the perilesional area of treated monkeys (p=0.045; p=0.001). Conclusions: Treatment with hUTC resulted in increased activation of microglia and complexity of reactive astrocyte processes as well as reduced post-lesion oxidative damage and hemosiderin deposition. This suggests the hUTC treatment enhanced recovery, in part, by recruitment of glial cells that limited the damage following cortical injury.

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.

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.

Acute brain inflammation, white matter oxidative stress, and myelin deficiency in a model of neonatal intraventricular hemorrhage

2020 ◽  
Vol 26 (6) ◽  
pp. 613-623 ◽  
Author(s):  
Danielle S. Goulding ◽  
R. Caleb Vogel ◽  
John C. Gensel ◽  
Josh M. Morganti ◽  
Arnold J. Stromberg ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
White Matter ◽  
Rat Model ◽  
Intraventricular Hemorrhage ◽  
Time Course ◽  
Brain Inflammation ◽  
Current Therapy ◽  
Posthemorrhagic Hydrocephalus ◽  
And Oxidative Stress

OBJECTIVENeonatal intraventricular hemorrhage (IVH) leads to posthemorrhagic hydrocephalus (PHH), brain injury, and long-term disability. Current therapy for IVH is based on treating PHH but does not address the underlying brain injury. In order to develop pharmacological treatment for IVH, there must be a better understanding of the underlying pathology of this disease. This study was designed to determine the time course of the acute inflammation and oxidative stress that may underlie the progressive pathology of IVH. The authors sought to understand the temporal relationships among inflammation, oxidative stress, and white matter pathology in a rat model of IVH.METHODSA rat model of IVH consisting of hemoglobin injection into the lateral ventricle was used. Tissue was analyzed via biochemical and histological methods to map the spatiotemporal distribution of innate immune activation and oxidative stress. White matter was quantified using both immunohistochemistry and Western blot for myelin basic protein (MBP) in the corpus callosum.RESULTSIVH led to acute induction of inflammatory cytokines, followed by oxidative stress. Oxidative stress was concentrated in white matter, adjacent to the lateral ventricles. Animals with IVH initially gained weight at a lower rate than control animals and had larger ventricles and less MBP than control animals.CONCLUSIONSExperimental IVH induces global inflammation throughout the brain and oxidative stress concentrated in the white matter. Both of these phenomena occur early after IVH. This has implications for human neonates with immature white matter that is exquisitely sensitive to inflammation and oxidative stress. Antiinflammatory or antioxidant therapy for IVH may need to be initiated early in order to protect developing white matter.

scholarly journals Targeting Mitochondrial Dysfunction and Oxidative Stress in Activated Microglia using Dendrimer-Based Therapeutics

Theranostics ◽  
2018 ◽  
Vol 8 (20) ◽  
pp. 5529-5547 ◽  
Author(s):  
Anjali Sharma ◽  
Kevin Liaw ◽  
Rishi Sharma ◽  
Zhi Zhang ◽  
Sujatha Kannan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Activated Microglia ◽  
And Oxidative Stress

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.

Co-exposure to deltamethrin and thiacloprid induces cytotoxicity and oxidative stress in human lung cells

2020 ◽  
Vol 36 (11) ◽  
pp. 916-924
Author(s):  
Vedat Şekeroğlu ◽  
Alperen Karabıyık ◽  
Zülal Atlı Şekeroğlu
Keyword(s):  
Oxidative Stress ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Limited Information ◽  
Human Telomerase Reverse Transcriptase ◽  
Human Lung Fibroblast ◽  
Human Lung Fibroblasts ◽  
Human Lung Cells ◽  
Human Telomerase ◽  
And Oxidative Stress

Deltamethrin (DEL) and thiacloprid (THIA) are commonly used synthetic insecticides in agriculture either separately or in combination. There is limited information in human cells for the effects of the mixture of DEL + THIA on oxidative stress. Therefore, the present study was designed to examine the effects of the mixture on cell proliferation and oxidative stress in human lung fibroblast cells. Human telomerase reverse transcriptase (hTERT)-expressing human lung fibroblasts, WTHBF-6 cells, were treated with 2.5 + 37.5, 5 + 75, 12.5 + 187.5, and 25 +375 µM concentrations of DEL + THIA for the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and 5 + 75, 12.5 + 187.5, and 25 + 375 µM for lipid peroxidation and reduced glutathione (GSH) assays for 24, 48, and 72 h in the absence and presence of metabolizing fractions of the mammalian liver (S9 mixture). Both the mixture of DEL + THIA and their metabolites significantly reduced cell viability and induced cytotoxicity in WTHBF-6 cells, especially at higher concentrations. The mixture of DEL + THIA significantly decreased GSH levels at the highest concentration for all treatment times and at the highest two concentrations (12.5 + 187.5 and 25 + 375 µM) for 72 h in the presence of S9 mixture. The highest concentration of DEL + THIA mixture caused a significant increase in malondialdehyde (MDA) level at 72 h in the absence of S9 mixture. There were also significant increases in MDA levels at the highest concentration for 48-h and all concentrations of DEL + THIA for 72-h treatment in WTHBF-6 cell cultures with S9. These data showed that the mixture of DEL + THIA and their metabolites can induce cytotoxicity and oxidative stress in human lung fibroblasts.

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