Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction

Miller, Stephanie; Yawno, Tamara; Alers, Nicole O; Castillo‐Melendez, Margie; Supramaniam, Veena; VanZyl, Niel; Sabaretnam, Tharani; Loose, Jan Michelle; Drummond, Grant Raymond; Walker, David; Jenkin, Graham; Wallace, Euan M.

doi:10.1111/jpi.12121

Cited by 140 publications

(191 citation statements)

References 54 publications

(81 reference statements)

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“…All in all, NADPH oxidase, LDL, and SERPINA1 are all associated with oxidative stress, which plays an important role in the pathological changes observed in FGR placentas. Several studies have suggest that using antioxidants (e.g., vitamins C and E) to treat pregnancies that are at high risk of FGR have shown positive effects of reducing the incidence of maternal disease and improving the prognosis of fetuses with FGR [43,44,45]. …”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Miao

Chen

Wang

et al. 2014

Cell Physiol Biochem

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Background: Fetal growth restriction (FGR) is the main cause of intrauterine fetal death and the second leading cause of death in the neonatal period. A large body of evidence suggests that FGR may be associated with the placenta, although its etiology and pathogenesis remain to be fully elucidated. Methods and Results: To better understand the molecular mechanisms underlying the pathological development of the placenta in FGR, we used tandem mass tags (TMTs) to construct a large-scale comparative proteomic profile of human placentas from normal and FGR pregnancies. A total of 1,198 kinds of proteins were identified in the control and FGR placentas, of which 95 were differentially expressed between two groups. Ingenuity Pathway Analysis (IPA) was used to organize these differentially expressed proteins into networks of interacting proteins and to identify the modules of functionally related proteins. Western blotting was used to verify the expression patterns of several randomly selected proteins. Conclusion: The placentas of women with FGR displayed significant proteome differences compared with normal pregnancy. The results indicate that a variety of mechanisms and proteins may contribute to the development of FGR. Further studies and validations are required to elucidate the exact roles of these proteins in FGR pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Miao

Chen

Wang

et al. 2014

Cell Physiol Biochem

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“…We have previously shown that FGR causes white matter injury in the term (late-onset) ovine FGR brain [20] , therefore we initially used Luxol Fast Blue staining as a general marker to qualitatively assess global myelin structure and demyelination, and to assign areas of interest. For Luxol Fast Blue staining, sections were dewaxed and cleared in serial ethanol before staining in a solution of Luxol Fast Blue MBSN (0.1% w/v, Aldrich), 10% acetic acid, and ethanol (95%) overnight at 60 ° C. Sections were rinsed in 95% ethanol and differentiated in 0.05% lithium chloride solution followed by 70% ethanol.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…On imaging, the FGR infant brain shows reduced total brain volume and grey matter volume [11] , and reduced hippocampal and cerebellar volume [13][14][15][16] , which might be contributed by neuronal cell loss [17] or delayed cellular complexity. Animal models of FGR, predominantly late-onset FGR, demonstrate white matter deficits as evidenced by delayed myelination [18,19] , hypomyelination, and reduced total white matter volume [20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

et al. 2017

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Fetal growth restriction (FGR) is a common complication of pregnancy, principally caused by suboptimal placental function, and is associated with high rates of perinatal mortality and morbidity. Clinical studies suggest that the time of onset of placental insufficiency is an important contributor towards the neurodevelopmental impairments that are evident in children who had FGR. It is however currently unknown how early-onset and late-onset FGR differentially affect brain development. The aim of this study was to examine neuropathology in early-onset and late-onset FGR fetal sheep and to determine whether they differentially alter brain development. We induced placental insufficiency and FGR via single umbilical artery ligation at either 88 days (early-onset) or 105 days (late-onset) of fetal sheep gestation (term is approx. 147 days), reflecting a period of rapid white matter brain development. Fetal blood samples were collected for the first 10 days after surgery, and all fetuses were sacrificed at 125 days' gestation for brain collection and subsequent histopathology. Our results show that early-onset FGR fetuses became progressively hypoxic over the first 10 days after onset of placental insufficiency, whereas late-onset FGR fetuses were significantly hypoxic compared to controls from day 1 after onset of placental insufficiency (SaO₂ 46.7 ± 7.4 vs. 65.7 ± 3.9%, respectively, p = 0.03). Compared to control brains, early-onset FGR brains showed widespread white matter injury, with a reduction in both CNPase-positive and MBP-positive density of staining in the periventricular white matter (PVWM), subcortical white matter, intragyral white matter (IGWM), subventricular zone (SVZ), and external capsule (p < 0.05 for all). Total oligodendrocyte lineage cell counts (Olig-2-positive) did not differ across groups, but mature oligodendrocytes (MBP-positive) were reduced, and neuroinflammation was evident in early-onset FGR brains with reactive astrogliosis (GFAP-positive) in the IGWM and cortex (p < 0.05), together with an increased number of Iba-1-positive activated microglia in the PVWM, SVZ, and cortex (p < 0.05). Late-onset FGR was associated with a widespread reduction of CNPase-positive myelin expression (p < 0.05) and a reduced number of mature oligodendrocytes in all white matter regions examined (p < 0.05). NeuN-positive neuronal cell counts in the cortex were not different across groups; however, the morphology of neuronal cells was different in response to placental insufficiency, most notable in the early-onset FGR fetuses, but it was late-onset FGR that induced caspase-3-positive apoptosis within the cortex. This study demonstrates that early-onset FGR is associated with more widespread white matter injury and neuroinflammation; however, both early- and late-onset FGR are associated with complex patterns of white and grey matter injury. These results indicate that it is the timing of the onset of fetal compromise relative to brain development that principally mediates altered ...

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“…For the fetal or neonatal brain, melatonin has a number of additional important properties. It readily crosses the placenta and the blood-brain barrier and it does not have any apparent adverse effect for the mother or baby, even in high concentrations [29,30,31]. …”

Section: Prenatal Therapiesmentioning

confidence: 99%

“…Melatonin administration to pregnant sheep mitigates the brain production of hydroxyl radical and cellular lipid peroxidation in response to acute fetal hypoxia [31]. Antenatal melatonin decreases white-matter brain injury characterized by hypomyelination and axonal damage and improves motor and cognitive function in newborn lambs after experimental intrauterine growth restriction in sheep [29]. …”

Section: Prenatal Therapiesmentioning

confidence: 99%

Ventilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies

Barton

Tolcos²,

Miller

et al. 2016

Neonatology

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Mechanical ventilation is a risk factor for cerebral inflammation and brain injury in preterm neonates. The risk increases proportionally with the intensity of treatment. Recent studies have shown that cerebral inflammation and injury can be initiated in the delivery room. At present, initiation of intermittent positive pressure ventilation (IPPV) in the delivery room is one of the least controlled interventions a preterm infant will likely face. Varying pressures and volumes administered shortly after birth are sufficient to trigger pathways of ventilation-induced lung and brain injury. The pathways involved in ventilation-induced brain injury include a complex inflammatory cascade and haemodynamic instability, both of which have an impact on the brain. However, regardless of the strategy employed to deliver IPPV, any ventilation has the potential to have an impact on the immature brain. This is particularly important given that preterm infants are already at a high risk for brain injury simply due to immaturity. This highlights the importance of improving the initial respiratory support in the delivery room. We review the mechanisms of ventilation-induced brain injury and discuss the need for, and the most likely, current therapeutic agents to protect the preterm brain. These include therapies already employed clinically, such as maternal glucocorticoid therapy and allopurinol, as well as other agents, such as erythropoietin, human amnion epithelial cells and melatonin, already showing promise in preclinical studies. Their mechanisms of action are discussed, highlighting their potential for use immediately after birth.

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Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction

Cited by 140 publications

References 54 publications

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

Ventilation-Induced Brain Injury in Preterm Neonates: A Review of Potential Therapies

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