scholarly journals Transient late gestation prenatal hypoxic insult results in functional deficits but not gross neuroanatomic deficits in mice

2021 ◽  
Author(s):  
Ana G Cristancho ◽  
Elyse C Gadra ◽  
Ima M Samba ◽  
Chenying Zhao ◽  
Minhui Ouyang ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Visual Learning ◽  
Fetal Brain ◽  
Developing Brain ◽  
Late Gestation ◽  
Prenatal Hypoxia ◽  
Seizure Threshold ◽  
Intrauterine Hypoxia

Intrauterine hypoxia is a common cause of brain injury in children with a wide spectrum of long-term neurodevelopmental sequela even after milder injury that does not result in significant neuroanatomical injury. Published prenatal hypoxia models generally require many days of modest hypoxia or are invasive, difficult to replicate surgery to ligate the uterine artery. Postnatal models of neonatal hypoxic brain injury are not able to study the effects of antenatal risk factors that contribute to outcomes of hypoxia to the developing brain. In addition, the most common postnatal hypoxia models induce significant cell death and large focal neuroanatomic injury through unilateral ischemia, which is not a common pattern of injury in children. Large animal models suggest that brief transient prenatal hypoxia alone is sufficient to lead to significant functional impairment to the developing brain. Thus, to further understand the mechanisms underlying hypoxic injury to the developing brain, it is vital to develop murine models that are simple to reproduce and phenocopy the lack of neuroanatomic injury but significant functional injury seen in children affected by mild intrauterine hypoxia. Here we characterized the effect of late gestation (embryonic day 17.5) transient prenatal hypoxia on long-term anatomical and neurodevelopmental outcomes. Prenatal hypoxia induced hypoxia inducible factor 1 alpha in the fetal brain. There was no difference in gestational age at birth, litter size at birth, survival, fetal brain cell death, or long-term changes in gray or white matter between offspring after normoxia and hypoxia. However, there were several long-term functional consequences from prenatal hypoxia, including sex-dichotomous changes. Both males and females have abnormalities in repetitive behaviors, hindlimb strength, and decreased seizure threshold. Males demonstrated increased anxiety. Females have deficit in social interaction. Hypoxia did not result in motor or visual learning deficits. This work demonstrates that transient late gestation prenatal hypoxia is a simple, clinically-relevant paradigm for studying putative environmental and genetic modulators of the long-term effects of transient hypoxia on the developing brain.

scholarly journals Particularities of morphogenesis of human fetus brain

2002 ◽  
Vol 51 (2) ◽  
pp. 89-94
Author(s):  
O. E. Talantova
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Environmental Factors ◽  
Human Brain ◽  
Fetal Brain ◽  
Cns Development ◽  
Cellular Processes ◽  
Human Brain Development ◽  
Future Child ◽  
Regressive Events

The review is devoted to the basic events of human fetal CNS development. The cellular processes of two broad phases of cerebral morphogenesis cytogenesis/histogenesis and differentiation/growth are described. In this review we also concern the main regressive events in the CNS development such as programmed cell death (apoptosis), axonal pruning and synaptic elimination. Different environmental factors may effect human brain development even from its early stages causing brain injury that can result in major or minor cerebral malformations. So, the knowledge of the main questions of fetal brain morphogenesis can helpto prevent some abnomalities of CNS in the future child development.

Role of neurosteroids in regulating cell death and proliferation in the late gestation fetal brain

Neuroscience ◽  
2009 ◽  
Vol 163 (3) ◽  
pp. 838-847 ◽  
Author(s):  
T. Yawno ◽  
J.J. Hirst ◽  
M. Castillo-Melendez ◽  
D.W. Walker
Keyword(s):  
Cell Death ◽  
Fetal Brain ◽  
Late Gestation

scholarly journals Repetitive Mild Traumatic Brain Injury in the Developing Brain: Effects on Long-Term Functional Outcome and Neuropathology

2016 ◽  
Vol 33 (7) ◽  
pp. 641-651 ◽  
Author(s):  
Emin Fidan ◽  
Jesse Lewis ◽  
Anthony E. Kline ◽  
Robert H. Garman ◽  
Henry Alexander ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Functional Outcome ◽  
Mild Traumatic Brain Injury ◽  
Developing Brain

Some practical and theoretical issues concerning fetal brain tissue grafts as therapy for brain dysfunctions

1995 ◽  
Vol 18 (1) ◽  
pp. 36-45 ◽  
Author(s):  
Donald G. Stein ◽  
Marylou M. Glasier
Keyword(s):  
Brain Injury ◽  
Multiple Testing ◽  
Nonhuman Primates ◽  
Fetal Brain ◽  
Neural Tissue ◽  
Target Article ◽  
Tissue Grafts ◽  
Theoretical Issues ◽  
Host Brain

AbstractGrafts of embryonic neural tissue into the brains of adult patients are currently being used to treat Parkinson's disease and are under serious consideration as therapy for a variety of other degenerative and traumatic disorders. This target article evaluates the use of transplants to promote recovery from brain injury and highlights the kinds of questions and problems that must be addressed before this form of therapy is routinely applied. It has been argued that neural transplantation can promote functional recovery through the replacement of damaged nerve cells, the reestablishment of specific nerve pathways lost as a result of injury, the release of specific neurotransmitters, or the production of factors that promote neuronal growth. The latter two mechanisms, which need not rely on anatomical connections to the host brain, are open to examination for nonsurgical, less intrusive therapeutic use. Certain subjective judgments used to select patients who will receive grafts and in assessment of the outcome of graft therapy make it difficult to evaluate the procedure. In addition, little long-term assessment of transplant efficacy and effect has been done in nonhuman primates. Carefully controlled human studies, with multiple testing paradigms, are also needed to establish the efficacy of transplant therapy.

scholarly journals Sulforaphane (SFA) protects neuronal cells from oxygen & glucose deprivation (OGD)

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248777
Author(s):  
Zeenat Ladak ◽  
Elizabeth Garcia ◽  
Jenny Yoon ◽  
Takaaki Landry ◽  
Edward A. Armstrong ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Protective Effect ◽  
Dietary Supplement ◽  
Attention Deficit Disorder ◽  
Fetal Brain ◽  
Cell Multiplication ◽  
Pregnant Rat ◽  
Broccoli Sprouts

Background Perinatal brain injury results in neurodevelopmental disabilities (neuroDDs) that include cerebral palsy, autism, attention deficit disorder, epilepsy, learning disabilities and others. Commonly, injury occurs when placental circulation, that is responsible for transporting nutrients and oxygen to the fetus, is compromised. Placental insufficiency (PI) is a reduced supply of blood and oxygen to the fetus and results in a hypoxic-ischemic (HI) environment. A significant HI state in-utero leads to perinatal compromise, characterized by fetal growth restriction and brain injury. Given that over 80% of perinatal brain injuries that result in neuroDDs occur during gestation, prior to birth, preventive approaches are needed to reduce or eliminate the potential for injury and subsequent neuroDDs. Sulforaphane (SFA) derived from cruciferous vegetables such as broccoli sprouts (BrSps) is a phase-II enzyme inducer that acts via cytoplasmic Nrf2 to enhance the production of anti-oxidants in the brain through the glutathione pathway. We have previously shown a profound in vivo neuro-protective effect of BrSps/SFA as a dietary supplement in pregnant rat models of both PI and fetal inflammation. Strong evidence also points to a role for SFA as treatment for various cancers. Paradoxically, then SFA has the ability to enhance cell survival, and with conditions of cancer, enhance cell death. Given our findings of the benefit of SFA/Broccoli Sprouts as a dietary supplement during pregnancy, with improvement to the fetus, it is important to determine the beneficial and toxic dosing range of SFA. We therefore explored, in vitro, the dosing range of SFA for neuronal and glial protection and toxicity in normal and oxygen/glucose deprived (OGD) cell cultures. Methods OGD simulates, in vitro, the condition experienced by the fetal brain due to PI. We developed a cell culture model of primary cortical neuronal, astrocyte and combined brain cell co-cultures from newborn rodent brains. The cultures were exposed to an OGD environment for various durations of time to determine the LD50 (duration of OGD required for 50% cell death). Using the LD50 as the time point, we evaluated the efficacy of varying doses of SFA for neuroprotective and neurotoxicity effects. Control cultures were exposed to normal media without OGD, and cytotoxicity of varying doses of SFA was also evaluated. Immunofluorescence (IF) and Western blot analysis of cell specific markers were used for culture characterization, and quantification of LD50. Efficacy and toxicity effect of SFA was assessed by IF/high content microscopy and by AlamarBlue viability assay, respectively. Results We determined the LD50 to be 2 hours for neurons, 8 hours for astrocytes, and 10 hours for co-cultures. The protective effect of SFA was noticeable at 2.5 μM and 5 μM for neurons, although it was not significant. There was a significant protective effect of SFA at 2.5 μM (p<0.05) for astrocytes and co-cultures. Significant toxicity ranges were also confirmed in OGD cultures as ≥ 100 μM (p<0.05) for astrocytes, ≥ 50 μM (p<0.01) for co-cultures, but not toxic in neurons; and toxic in control cultures as ≥ 100 μM (p<0.01) for neurons, and ≥ 50 μM (p<0.01) for astrocytes and co-cultures. One Way ANOVA and Dunnett’s Multiple Comparison Test were used for statistical analysis. Conclusions Our results indicate that cell death shows a trend to reduction in neuronal and astrocyte cultures, and is significantly reduced in co-cultures treated with low doses of SFA exposed to OGD. Doses of SFA that were 10 times higher were toxic, not only under conditions of OGD, but in normal control cultures as well. The findings suggest that: 1. SFA shows promise as a preventative agent for fetal ischemic brain injury, and 2. Because the fetus is a rapidly growing organism with profound cell multiplication, dosing parameters must be established to insure safety within efficacious ranges. This study will influence the development of innovative therapies for the prevention of childhood neuroDD.

scholarly journals Intranasally Administered Exosomes from Umbilical Cord Stem Cells Have Preventive Neuroprotective Effects and Contribute to Functional Recovery after Perinatal Brain Injury

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 855 ◽  
Author(s):  
Thomi ◽  
Joerger-Messerli ◽  
Haesler ◽  
Muri ◽  
Surbek ◽  
...  
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Neurodevelopmental Outcome ◽  
Neuronal Cell ◽  
Learning Ability ◽  
Specific Cell ◽  
Perinatal Brain Injury ◽  
Neuroprotective Effects ◽  
Cell Counts

Perinatal brain injury (PBI) in preterm birth is associated with substantial injury and dysmaturation of white and gray matter, and can lead to severe neurodevelopmental deficits. Mesenchymal stromal cells (MSC) have been suggested to have neuroprotective effects in perinatal brain injury, in part through the release of extracellular vesicles like exosomes. We aimed to evaluate the neuroprotective effects of intranasally administered MSC-derived exosomes and their potential to improve neurodevelopmental outcome after PBI. Exosomes were isolated from human Wharton’s jelly MSC supernatant using ultracentrifugation. Two days old Wistar rat pups were subjected to PBI by a combination of inflammation and hypoxia-ischemia. Exosomes were intranasally administered after the induction of inflammation and prior to ischemia, which was followed by hypoxia. Infrared-labeled exosomes were intranasally administered to track their distribution with a LI-COR scanner. Acute oligodendrocyte- and neuron-specific cell death was analyzed 24 h after injury in animals with or without MSC exosome application using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemical counterstaining. Myelination, mature oligodendroglial and neuronal cell counts were assessed on postnatal day 11 using immunohistochemistry, Western blot or RT-PCR. Morris water maze assay was used to evaluate the effect of MSC exosomes on long-term neurodevelopmental outcome 4 weeks after injury. We found that intranasally administered exosomes reached the frontal part of the brain within 30 min after administration and distributed throughout the whole brain after 3 h. While PBI was not associated with oligodendrocyte-specific cell death, it induced significant neuron-specific cell death which was substantially reduced upon MSC exosome application prior to ischemia. MSC exosomes rescued normal myelination, mature oligodendroglial and neuronal cell counts which were impaired after PBI. Finally, the application of MSC exosomes significantly improved learning ability in animals with PBI. In conclusion, MSC exosomes represent a novel prevention strategy with substantial clinical potential as they can be administered intranasally, prevent gray and white matter alterations and improve long-term neurodevelopmental outcome after PBI.

scholarly journals Programmed Necrosis: A Prominent Mechanism of Cell Death following Neonatal Brain Injury

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Raul Chavez-Valdez ◽  
Lee J. Martin ◽  
Frances J. Northington
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Significant Proportion ◽  
Developing Brain ◽  
Neonatal Brain ◽  
Programmed Necrosis ◽  
Interacting Protein ◽  
Neonatal Brain Injury ◽  
Regulated Necrosis

Despite the introduction of therapeutic hypothermia, neonatal hypoxic ischemic (HI) brain injury remains a common cause of developmental disability. Development of rational adjuvant therapies to hypothermia requires understanding of the pathways of cell death and survival modulated by HI. The conceptualization of the apoptosis-necrosis “continuum” in neonatal brain injury predicts mechanistic interactions between cell death and hydrid forms of cell death such as programmed or regulated necrosis. Many of the components of the signaling pathway regulating programmed necrosis have been studied previously in models of neonatal HI. In some of these investigations, they participate as part of the apoptotic pathways demonstrating clear overlap of programmed death pathways. Receptor interacting protein (RIP)-1 is at the crossroads between types of cellular death and survival and RIP-1 kinase activity triggers formation of the necrosome (in complex with RIP-3) leading to programmed necrosis. Neuroprotection afforded by the blockade of RIP-1 kinase following neonatal HI suggests a role for programmed necrosis in the HI injury to the developing brain. Here, we briefly review the state of the knowledge about the mechanisms behind programmed necrosis in neonatal brain injury recognizing that a significant proportion of these data derive from experiments in cultured cell and some from in vivo adult animal models. There are still more questions than answers, yet the fascinating new perspectives provided by the understanding of programmed necrosis in the developing brain may lay the foundation for new therapies for neonatal HI.

scholarly journals Features of pathogenesis and early diagnostic criteria of hypoxic-ischemic brain injury in newborns (part 2)

2021 ◽  
Vol 16 (8) ◽  
pp. 5-14
Author(s):  
V.Yu. Martyniuk ◽  
V.B. Shveikina ◽  
T.K. Znamenska ◽  
L.I. Nikulina
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Brain Injury ◽  
Early Diagnosis ◽  
Intercellular Adhesion ◽  
Developing Brain ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury

The article deals with the current problem of neonatology and pediatric neurology — the issues of early diagnosis of perinatal hypoxic-ischemic brain injury in newborns, particularly, in prematurely born children. The work considers modern literature data on the mechanisms of hypoxic-ischemic perinatal brain damage. New data on the functioning, injury, as well as the mechanism of cell death of neuronal and glial origin in the developing brain are presented. It was shown that excitotoxicity (glutamatergic system), oxidative stress and aseptic inflammation are involved in the realization of this mechanism, the final result of which is cell death by necrosis and pathological apoptosis. It was emphasized that in immature neuronal tissue, the death of neurons occurs not only by the above paths, but also due to the combined necrotic-apoptotic (necroptotic) mechanism. The ambiguous role of glutamate receptors in the developing brain is analyzed. Literature data are presented that excitotoxicity, oxidative stress and inflammation against the background of peculiarities mitochondrial functioning in the brain lead to the onset of pathological apoptosis. It has been determined that the most promising in the early diagnosis of hypoxic-ischemic damage to the central nervous system in newborns, in particular premature babies, is the study of the level of neuron-specific proteins and antibodies to them, as well as proteins associated with the plasma membrane — intercellular adhesion molecules. The article analyzes the role of neuronal and glial markers, in particular glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1, myelin basic protein, as well as the role of pro-inflammatory cytokines in the mechanisms of damage to cells of the developing brain. The role of the membrane protein of cerebral capillary endotheliocytes, an intercellular adhesion molecule 1, as one of the markers of damage to the blood-brain barrier cells in various pathological processes, in particular hypoxia and ischemia, was determined.

scholarly journals Fetal Brain Injury in Survivors of Twin Pregnancies Complicated by Demise of One Twin: A Review

2016 ◽  
Vol 19 (3) ◽  
pp. 262-267 ◽  
Author(s):  
Fiona L. Mackie ◽  
R. Katie Morris ◽  
Mark. D. Kilby
Keyword(s):  
Brain Injury ◽  
Brain Injuries ◽  
Fetal Brain ◽  
Neurological Complications ◽  
Pathological Process ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Increased Risk ◽  
Twin Pregnancies

Perinatal mortality is increased considerably in multiple pregnancies compared to singleton pregnancies, with single intrauterine fetal demise (sIUFD) presenting a rare but unique perinatal problem. Monochorionic pregnancies are at particular risk of sIUFD due to bidirectional inter-twin placental vascular anastomoses. The resulting inter-twin blood flow can become unbalanced, causing acute and chronic inter-twin transfusion and profound anemia secondary to fetal exsanguination into the low-pressure circulation of the dead fetus. If the sIUFD occurs after 14 weeks’ gestation it is believed to have the most significant effect on the continuing pregnancy as the co-twin is at increased risk of preterm delivery, long-term neurological complications, and death. This article will focus on fetal brain injury in the surviving co-twin in the case of sIUFD, as it is the most common kind of injury in sIUFD, and one which concerns parents and may be the basis for terminating the pregnancy. We will outline how these brain injuries are thought to occur and describe potential pathophysiological mechanisms. We will discuss risk factors for brain injury in cases of sIUFD, including: chorionicity, cause of the sIUFD (spontaneous or secondary to an underlying pathological process such as twin-to-twin transfusion syndrome), gestation of delivery and how to prevent brain injury in the co-twin. We also review modes of imaging, discuss the difficulties in predicting the long-term outcome for co-twin survivors, and highlight the dearth of research in this area.

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