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Cells
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Mechanisms of Cell Death in Neonatal Brain Injury
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Mechanisms of Cell Death in Neonatal Brain Injury

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 25008

Special Issue Editor

Dr. Claire Thornton

E-Mail Website
Guest Editor
Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, UK
Interests: neonatal brain; mitochondrial dynamics; cell death; signalling; neurocellular stress; hypoxia–ischaemia; pollution; addiction

Special Issue Information

Dear Colleagues,

Neonatal brain injury remains a significant cause of long-term neurological and physical disability, placing significant emotional and socioeconomic burdens on families and society. Limited therapies exist to counteract such injuries, and although many are investigated in the laboratory, few make it to clinic. Development of a successful therapy is hindered by the complexity of molecular pathways initiated in the neonatal brain in response to stresses such as infection, toxicant exposure or nutrient/oxygen deprivation.

Our understanding of cell death mechanisms has undergone a revolution over the last decade, and we now need to evaluate how these more recently identified pathways (necroptosis, pyroptosis, ferroptosis, and autophagic cell death, among a myriad of others) impact the neonatal brain. It is also clear that cell death mechanism(s) are intertwined with factors incorporating the severity of insult, cell type, metabolic profile, sex, and developmental window.

Articles collected together in this Special Issue will focus on discerning the molecular mechanisms and regulators of cell death triggered in the immature brain in response to a variety of neonatal brain injury paradigms. Such data are vital if new avenues for therapeutic intervention are to be identified for the successful treatment of neonatal brain injury and associated neurodevelopmental disorders.

Dr. Claire Thornton
Guest Editor

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Keywords

  • neonatal brain injury
  • hypoxic–ischaemic encephalopathy
  • inflammation
  • neurodevelopment
  • neurotoxicity
  • neonatal stroke
  • preterm birth
  • mitochondria
  • cell death
  • ER stress

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Published Papers (6 papers)

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Research

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17 pages, 7395 KiB  
Article
Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia–Ischemia
by Syam Nair, Anna-Lena Leverin, Eridan Rocha-Ferreira, Kristina S. Sobotka, Claire Thornton, Carina Mallard and Henrik Hagberg
Cells 2022, 11(7), 1193; https://doi.org/10.3390/cells11071193 - 1 Apr 2022
Cited by 13 | Viewed by 4138
Abstract
Hypoxia–ischemia (HI) leads to immature brain injury mediated by mitochondrial stress. If damaged mitochondria cannot be repaired, mitochondrial permeabilization ensues, leading to cell death. Non-optimal turnover of mitochondria is critical as it affects short and long term structural and functional recovery and brain [...] Read more.
Hypoxia–ischemia (HI) leads to immature brain injury mediated by mitochondrial stress. If damaged mitochondria cannot be repaired, mitochondrial permeabilization ensues, leading to cell death. Non-optimal turnover of mitochondria is critical as it affects short and long term structural and functional recovery and brain development. Therefore, disposal of deficient mitochondria via mitophagy and their replacement through biogenesis is needed. We utilized mt-Keima reporter mice to quantify mitochondrial morphology (fission, fusion) and mitophagy and their mechanisms in primary neurons after Oxygen Glucose Deprivation (OGD) and in brain sections after neonatal HI. Molecular mechanisms of PARK2-dependent and -independent pathways of mitophagy were investigated in vivo by PCR and Western blotting. Mitochondrial morphology and mitophagy were investigated using live cell microscopy. In primary neurons, we found a primary fission wave immediately after OGD with a significant increase in mitophagy followed by a secondary phase of fission at 24 h following recovery. Following HI, mitophagy was upregulated immediately after HI followed by a second wave at 7 days. Western blotting suggests that both PINK1/Parkin-dependent and -independent mechanisms, including NIX and FUNDC1, were upregulated immediately after HI, whereas a PINK1/Parkin mechanism predominated 7 days after HI. We hypothesize that excessive mitophagy in the early phase is a pathologic response which may contribute to secondary energy depletion, whereas secondary mitophagy may be involved in post-HI regeneration and repair. Full article
(This article belongs to the Special Issue Mechanisms of Cell Death in Neonatal Brain Injury)
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14 pages, 2324 KiB  
Article
Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model
by Erik Axel Andersson, Eridan Rocha-Ferreira, Henrik Hagberg, Carina Mallard and Carl Joakim Ek
Cells 2021, 10(7), 1677; https://doi.org/10.3390/cells10071677 - 2 Jul 2021
Cited by 8 | Viewed by 4496
Abstract
Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the [...] Read more.
Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB function occurred. The sucrose experiment indicated that regions somewhat more distant to the hematoma also exhibited BBB dysfunction; however, BBB function was normalised within 5 days of GMH. This shows that GMH leads to a temporal dysfunction in the BBB that may be important in pathological processes as well as in connection to therapeutic interventions. We detected an increase of tight-junction proteins in both CSF and plasma after GMH making them potential biomarkers for GMH. Full article
(This article belongs to the Special Issue Mechanisms of Cell Death in Neonatal Brain Injury)
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14 pages, 1978 KiB  
Article
Moderately Inducing Autophagy Reduces Tertiary Brain Injury after Perinatal Hypoxia-Ischemia
by Brian H. Kim, Maciej Jeziorek, Hur Dolunay Kanal, Viorica Raluca Contu, Radek Dobrowolski and Steven W. Levison
Cells 2021, 10(4), 898; https://doi.org/10.3390/cells10040898 - 14 Apr 2021
Cited by 13 | Viewed by 2823
Abstract
Recent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an [...] Read more.
Recent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an antagonist for TGFβ receptor activin-like kinase 5 (ALK5)—SB505124—three days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated light chain 3 (LC3), a key protein known to mediate autophagy. However, those studies did not determine whether (1) SB was acting directly on the CNS and (2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist three days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting three days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial. Full article
(This article belongs to the Special Issue Mechanisms of Cell Death in Neonatal Brain Injury)
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Review

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26 pages, 2212 KiB  
Review
Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity
by Riley Sevensky, Jessie C. Newville, Ho Lam Tang, Shenandoah Robinson and Lauren L. Jantzie
Cells 2021, 10(8), 1911; https://doi.org/10.3390/cells10081911 - 28 Jul 2021
Cited by 10 | Viewed by 4779
Abstract
Globally, approximately 11% of all infants are born preterm, prior to 37 weeks’ gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP [...] Read more.
Globally, approximately 11% of all infants are born preterm, prior to 37 weeks’ gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP encompasses numerous types of preterm birth-related brain abnormalities and injuries, and can culminate in a diverse array of neurodevelopmental impairments. Of note, posthemorrhagic hydrocephalus of prematurity (PHHP) can be conceptualized as a severe manifestation of EoP. PHHP impacts the immature neonatal brain at a crucial timepoint during neurodevelopment, and can result in permanent, detrimental consequences to not only cerebrospinal fluid (CSF) dynamics, but also to white and gray matter development. In this review, the relevant literature related to the diverse mechanisms of cell death in the setting of PHHP will be thoroughly discussed. Loss of the epithelial cells of the choroid plexus, ependymal cells and their motile cilia, and cellular structures within the glymphatic system are of particular interest. Greater insights into the injuries, initiating targets, and downstream signaling pathways involved in excess cell death shed light on promising areas for therapeutic intervention. This will bolster current efforts to prevent, mitigate, and reverse the consequential brain remodeling that occurs as a result of hydrocephalus and other components of EoP. Full article
(This article belongs to the Special Issue Mechanisms of Cell Death in Neonatal Brain Injury)
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17 pages, 1523 KiB  
Review
Efferocytosis Mediated Modulation of Injury after Neonatal Brain Hypoxia-Ischemia
by Jana Krystofova Mike and Donna Marie Ferriero
Cells 2021, 10(5), 1025; https://doi.org/10.3390/cells10051025 - 27 Apr 2021
Cited by 15 | Viewed by 4792
Abstract
Neonatal brain hypoxia-ischemia (HI) is a leading cause of morbidity and long-term disabilities in children. While we have made significant progress in describing HI mechanisms, the limited therapies currently offered for HI treatment in the clinical setting stress the importance of discovering new [...] Read more.
Neonatal brain hypoxia-ischemia (HI) is a leading cause of morbidity and long-term disabilities in children. While we have made significant progress in describing HI mechanisms, the limited therapies currently offered for HI treatment in the clinical setting stress the importance of discovering new targetable pathways. Efferocytosis is an immunoregulatory and homeostatic process of clearance of apoptotic cells (AC) and cellular debris, best described in the brain during neurodevelopment. The therapeutic potential of stimulating defective efferocytosis has been recognized in neurodegenerative diseases. In this review, we will explore the involvement of efferocytosis after a stroke and HI as a promising target for new HI therapies. Full article
(This article belongs to the Special Issue Mechanisms of Cell Death in Neonatal Brain Injury)
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Other

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18 pages, 593 KiB  
Systematic Review
Assessing Creatine Supplementation for Neuroprotection against Perinatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review of Perinatal and Adult Pre-Clinical Studies
by Nhi Thao Tran, Sharmony B. Kelly, Rod J. Snow, David W. Walker, Stacey J. Ellery and Robert Galinsky
Cells 2021, 10(11), 2902; https://doi.org/10.3390/cells10112902 - 27 Oct 2021
Cited by 10 | Viewed by 2846
Abstract
There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify [...] Read more.
There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify knowledge gaps that need to be addressed before creatine can be considered for pragmatic clinical trials for HIE. Methods: We reviewed preclinical studies up to 20 September 2021 using PubMed, EMBASE and OVID MEDLINE databases. The SYRCLE risk of bias assessment tool was utilized. Results: Seventeen studies were identified. Dietary creatine was the most common administration route. Cerebral creatine loading was age-dependent with near term/term-equivalent studies reporting higher increases in creatine/phosphocreatine compared to adolescent-adult equivalent studies. Most studies did not control for sex, study long-term histological and functional outcomes, or test creatine post-HI. None of the perinatal studies that suggested benefit directly controlled core body temperature (a known confounder) and many did not clearly state controlling for potential study bias. Conclusion: Creatine is a promising neuroprotective intervention for HIE. However, this systematic review reveals key knowledge gaps and improvements to preclinical studies that must be addressed before creatine can be trailed for neuroprotection of the human fetus/neonate. Full article
(This article belongs to the Special Issue Mechanisms of Cell Death in Neonatal Brain Injury)
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