Molecular Mechanisms of Neonatal Brain Injury

Thornton, Claire; Rousset, Colette; Kichev, Anton; Miyakuni, Yasuka; Vontell, Regina; Baburamani, Ana A.; Fleiss, Bobbi; Gressèns, Pierre; Hagberg, Henrik

doi:10.1155/2012/506320

Cited by 109 publications

(102 citation statements)

References 200 publications

(206 reference statements)

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“…TNFa, TNFb, FasL, TRAIL, and TWEAK). [85][86][87][88][89][90] The interaction of these ligands with their receptors, including TNF receptor 1, FasR, death receptor 4, death receptor 5, and TWEAKR, expressed by oligodendrocyte progenitor cells and neurons, can trigger apoptotic cell death. Death receptor activation triggers an extrinsic pathway of caspase-dependent cell death, or produces truncated Bid, leading to enhancement of Bax-dependent mitochondrial pore formation and cell death.…”

Section: Death Receptorsmentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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COXPerinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PERINATAL BRAIN INJURY IN THE TERM-BORN INFANTIntrapartum neonatal deaths are the third leading cause of global childhood mortality. 1 In addition, each year perinatal insults are estimated to be responsible for more than one million new cases of neonatal encephalopathy, and nearly half a million infants with impairments such as cerebral palsy (CP).2 Infants exposed to a perinatal insult typically present with encephalopathy, a descriptive term for a clinical constellation of neurological dysfunctions in the term-born that includes difficulty with initiating and maintaining respiration; depression of tone and reflexes; subnormal levels of consciousness; and seizures.3 Whilst often assumed to result solely from acute intrapartum hypoxic-ischaemia, the precise contribution of hypoxia is likely to vary according to the definition of encephalopathy used, the range of competing risks, and the care setting. 3,4 Presumed hypoxia-ischaemia is diagnosed based on reduced Apgar scores and acidosis, 5 and the combination of progressive hypoxia, hypercarbia, and acidosis is often referred to as asphyxia. 6 Encephalopathy resulting from hypoxia-ischaemia can be clearly diagnosed only in a small number of cases in which a sentinel event, such as placental abruption, uterine rupture, cord prolapse, or shoulder dystocia, is clearly present. Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased.2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes. 12 CONCEPT OF INFLAMMATION-INDUCED SENSITIZATIONAn increasingly common model for the complex and multifactorial process of perinatal brain injury involves sensitization, 13-15 whereby factors not severe enough by themselves to induce significant brain damage make the developi...

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Section: Death Receptorsmentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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“…It has been known that the depletion of cellular energy production, decreased tissue glucose metabolism and the development of cell injury in the HI brain are closely related (Thornton et al, 2012). Consequently, there is an incontestable need to study the mechanisms underlying HI brain injury and search for additional possible therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen-rich saline mediates neuroprotection through the regulation of endoplasmic reticulum stress and autophagy under hypoxia-ischemia neonatal brain injury in mice

et al. 2016

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“…Unfortunately, hypothermia is only able to improve outcome for 1 out of every 7 infants treated, but critically provides proof-of-concept for treatment after injury [3]. Adjunct and alternative therapies are therefore a health care priority and, to date, those that target multiple pathways within the pathophysiology of NE [4] (such as hypothermia) have had the greatest preclinical and phase I/II success, i.e melatonin, dexmedetomidine and xenon [5,6,7,8,9]. Cell death is an important pathological process in NE and, in addition, inflammation is a chief pathophysiological process.…”

Section: Introductionmentioning

confidence: 99%

The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia

Fleiss

Chhor²,

Rajudin³

et al. 2015

Dev Neurosci

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Neonatal encephalopathy (NE) is a leading cause of childhood death and disability in term infants. Treatment options for perinatal brain injury are limited and developing therapies that target multiple pathways within the pathophysiology of NE are of great interest. Pifithrin-µ (PFT-µ) is a drug with striking neuroprotective abilities in a preclinical model of hypoxia-ischemia (HI)-induced NE wherein cell death is a substantial cause of injury. Work from neurons and tumor cells reports that PFT-µ is able to inhibit p53 binding to the mitochondria, heat shock protein (HSP)-70 substrate binding and activation of the NF-kB pathway. The purpose of this study is to understand whether the neuroprotective effects of PFT-µ also include direct effects on microglia. We utilized the microglial cell line, BV2, and we studied the dose-dependent effect of PFT-µ on M1-like and M2-like phenotype using qRT-PCR and Western blotting, including the requirement for the presence of p53 or HSP-70 in these effects. We also assessed phagocytosis and the effects of PFT-µ on genes within metabolic pathways related to phenotype. We noted that PFT-µ robustly reduced the M1-like (lipopolysaccharide, LPS-induced) BV2 response, spared the LPS-induced phagocytic ability of BV2 and had no effect on the genes related to metabolism and that effects on phenotype were partially dependent on the presence of HSP-70 but not p53. This study demonstrates that the neuroprotective effects of PFT-µ in HI-induced NE may include an anti-inflammatory effect on microglia and adds to the evidence that this drug might be of clinical interest for the treatment of NE.

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Molecular Mechanisms of Neonatal Brain Injury

Cited by 109 publications

References 200 publications

Inflammation‐induced sensitization of the brain in term infants

Inflammation‐induced sensitization of the brain in term infants

Hydrogen-rich saline mediates neuroprotection through the regulation of endoplasmic reticulum stress and autophagy under hypoxia-ischemia neonatal brain injury in mice

The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia

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