| 1. |
- Dean, J. M., et al.
(författare)
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A Critical Review of Models of Perinatal Infection
- 2015
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Ingår i: Developmental Neuroscience. - : S. Karger AG. - 0378-5866 .- 1421-9859. ; 37:4-5, s. 289-304
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Forskningsöversikt (refereegranskat)abstract
- One of the central, unanswered questions in perinatology is why preterm infants continue to have such poor long-term neurodevelopmental, cognitive and learning outcomes, even though severe brain injury is now rare. There is now strong clinical evidence that one factor underlying disability may be infection, as well as nonspecific inflammation, during fetal and early postnatal life. In this review, we examine the experimental evidence linking both acute and chronic infection/inflammation with perinatal brain injury and consider key experimental determinants, including the microglia response, relative brain and immune maturity and the pattern of exposure to infection. We highlight the importance of the origin and derivation of the bacterial cell wall component lipopolysaccharide. Such experimental paradigms are essential to determine the precise time course of the inflammatory reaction and to design targeted neuroprotective strategies to protect the perinatal brain from infection and inflammation. (C) 2015 S. Karger AG, Basel
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| 2. |
- Hagberg, Henrik, 1955, et al.
(författare)
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Apoptotic mechanisms in the immature brain: involvement of mitochondria.
- 2009
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Ingår i: Journal of child neurology. - : SAGE Publications. - 1708-8283 .- 0883-0738. ; 24:9, s. 1141-6
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Forskningsöversikt (refereegranskat)abstract
- Brain injury after hypoxic-ischemic encephalopathy often develops with delayed appearance, opening a therapeutic window. Clinical studies in newborns show that post-hypoxic-ischemic hypothermia improves outcome. This has generated renewed interest in the molecular mechanisms of hypoxic-ischemic brain injury. In this brief review, we propose that mitochondrial permeabilization is crucial for injury to advance beyond the point of no return. We suggest that excitatory amino acids, nitric oxide, inflammation, trophic factor withdrawal, and an increased pro- versus antiapoptotic Bcl-2 protein ratio will trigger Bax-dependent mitochondrial outer membrane permeabilization. Mitochondrial outer membrane permeabilization, in turn, elicits mitochondrial release of cytochrome C, apoptosis-inducing factor, second mitochondria-derived activator of caspase/Diablo, and HtrA2/Omi. Cytochrome C efflux activates caspase-9/-3, leading to DNA fragmentation. Apoptosis-inducing factor interacts with cyclophilin A and induces chromatinolysis. Blockage of mitochondrial outer membrane permeabilization holds promise as a strategy for perinatal brain protection.
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| 3. |
- Hagberg, Henrik, 1955, et al.
(författare)
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Effect of inflammation on central nervous system development and vulnerability
- 2005
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Ingår i: Curr Opin Neurol. - 1350-7540. ; 18:2, s. 117-23
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Forskningsöversikt (refereegranskat)abstract
- PURPOSE OF REVIEW: Preterm infants are at high risk for neurological sequelae and cognitive dysfunction. These problems have been attributed to a high occurrence of central nervous system (CNS) lesions, but suboptimal brain development appears to be just as important. In this brief review we present the hypothesis that systemic infection/inflammation can severely interfere with normal CNS function and development. RECENT FINDINGS: We focus on the effects of lipopolysaccharide because it is often used to model the systemic inflammatory response induced by infections. The inflammatory signals are propagated across the intact or ruptured blood-brain barrier to the CNS by proinflammatory cytokines, prostaglandins, or lipopolysaccharide. Subsequently, microglia are triggered to release cytokines, oxygen free radicals and trophic factors, which will influence the CNS in various ways. Cognition, dendritic length and spine density, dopaminergic cells, neurogenesis and glial proliferation will be affected. Furthermore, CNS vulnerability and, in some instances, cerebral anomalies and white matter damage are produced. SUMMARY: Hypothetically, all of these effects on the CNS triggered by inflammation may have severe consequences for the individual's ability to cope with environmental exposures during childhood and adulthood.
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| 4. |
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| 5. |
- Hagberg, Henrik, 1955, et al.
(författare)
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Preconditioning and the developing brain
- 2004
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Ingår i: Semin Perinatol. - : Elsevier BV. - 0146-0005. ; 28:6, s. 389-95
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Forskningsöversikt (refereegranskat)abstract
- Preconditioning occurs when a subinjurious exposure renders the brain less vulnerable to a subsequent damaging exposure. In this essay, various models of preconditioning in the immature brain are discussed. Adenosine, excitatory amino acids, nitric oxide, hypoxia-inducible factor, ATP-sensitive K+ channels, caspases, heat shock proteins, inflammatory mediators and gene expression all seem to be involved in sensing, transducing and executing preconditioning resistance. Also reviewed in this essay is evidence that some subinjurious exposures render the brain more vulnerable to a subsequent damaging exposure. We believe that unraveling the mechanisms of how the developing brain becomes inherently resilient or vulnerable will offer important insights into the pathogenesis of injury. Preconditioning of the brain or induction of tolerance of the immune system might be utilized in the future to decrease CNS vulnerability and the occurrence of perinatal brain injury.
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| 6. |
- Hagberg, Henrik, 1955, et al.
(författare)
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Role of cytokines in preterm labour and brain injury.
- 2005
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Ingår i: BJOG : an international journal of obstetrics and gynaecology. - : Wiley. - 1470-0328. ; 112 Suppl 1, s. 16-8
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Forskningsöversikt (refereegranskat)abstract
- Intrauterine infection induces an intra-amniotic inflammatory response involving the activation of a number of cytokines and chemokines which, in turn, may trigger preterm contractions, cervical ripening and rupture of the membranes. Infection and cytokine-mediated inflammation appear to play a prominent role in preterm birth at early gestations (<30 weeks). The role of infection/inflammation in preterm birth in Europe has been incompletely characterised. The rate of preterm birth in Sweden is lower, and the rate of chorioamnionitis, bacterial vaginosis (BV), neonatal sepsis, and urinary tract infections during pregnancy is lower compared with the USA. In a Swedish population of women with preterm labour or preterm premature rupture of the membranes (PPROM) <34 weeks of gestation, microorganisms were detected in the amniotic fluid in 25% of women with PPROM and in 16% of those in preterm labour. Nearly half of these women had intra-amniotic inflammation defined as elevated interleukin-6 (IL-6) and IL-8, and there was a high degree of correlation between cytokine levels and preterm birth or the presence of microbial colonisation. These data do not support the hypothesis that infection-related preterm birth is less frequent in northern Europe than elsewhere. The intra-amniotic inflammatory response has also been associated with white matter injury and cerebral palsy. We find that in experimental models, induction of a systemic inflammatory response using lipopolysaccharide activates toll-like receptors (TLRs), which produce either white matter lesions or increase brain susceptibility to secondary insults. Recently, IL-18 in umbilical blood was shown to correlate with brain injury in preterm infants and IL-18 deficiency in mice decreases CNS vulnerability.
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| 7. |
- Hagberg, Henrik, 1955, et al.
(författare)
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The role of inflammation in perinatal brain injury.
- 2015
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Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4758 .- 1759-4766. ; 11:4, s. 192-208
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Forskningsöversikt (refereegranskat)abstract
- Inflammation is increasingly recognized as being a critical contributor to both normal development and injury outcome in the immature brain. The focus of this Review is to highlight important differences in innate and adaptive immunity in immature versus adult brain, which support the notion that the consequences of inflammation will be entirely different depending on context and stage of CNS development. Perinatal brain injury can result from neonatal encephalopathy and perinatal arterial ischaemic stroke, usually at term, but also in preterm infants. Inflammation occurs before, during and after brain injury at term, and modulates vulnerability to and development of brain injury. Preterm birth, on the other hand, is often a result of exposure to inflammation at a very early developmental phase, which affects the brain not only during fetal life, but also over a protracted period of postnatal life in a neonatal intensive care setting, influencing critical phases of myelination and cortical plasticity. Neuroinflammation during the perinatal period can increase the risk of neurological and neuropsychiatric disease throughout childhood and adulthood, and is, therefore, of concern to the broader group of physicians who care for these individuals.
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| 8. |
- Lai, Jacqueline, 1980, et al.
(författare)
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Immune responses in perinatal brain injury.
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 63
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Forskningsöversikt (refereegranskat)abstract
- The perinatal period has often been described as immune deficient. However, it has become clear that immune responses in the neonate following exposure to microbes or as a result of tissue injury may be substantial and play a role in perinatal brain injury. In this article we will review the immune cell composition under normal physiological conditions in the perinatal period, both in the human and rodent. We will summarize evidence of the inflammatory responses to stimuli and discuss how neonatal immune activation, both in the central nervous system and in the periphery, may contribute to perinatal hypoxic-ischemic brain injury.
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| 9. |
- Leaw, B., et al.
(författare)
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Mitochondria, Bioenergetics and Excitotoxicity: New Therapeutic Targets in Perinatal Brain Injury
- 2017
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 11
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Forskningsöversikt (refereegranskat)abstract
- Injury to the fragile immature brain is implicated in the manifestation of long-term neurological disorders, including childhood disability such as cerebral palsy, learning disability and behavioral disorders. Advancements in perinatal practice and improved care mean the majority of infants suffering from perinatal brain injury will survive, with many subtle clinical symptoms going undiagnosed until later in life. Hypoxicischemia is the dominant cause of perinatal brain injury, and constitutes a significant socioeconomic burden to both developed and developing countries. Therapeutic hypothermia is the sole validated clinical intervention to perinatal asphyxia; however it is not always neuroprotective and its utility is limited to developed countries. There is an urgent need to better understand the molecular pathways underlying hypoxic-ischemic injury to identify new therapeutic targets in such a small but critical therapeutic window. Mitochondria are highly implicated following ischemic injury due to their roles as the powerhouse and main energy generators of the cell, as well as cell death processes. While the link between impaired mitochondrial bioenergetics and secondary energy failure following loss of high-energy phosphates is well established after hypoxia-ischemia (HI), there is emerging evidence that the roles of mitochondria in disease extend far beyond this. Indeed, mitochondrial turnover, including processes such as mitochondrial biogenesis, fusion, fission and mitophagy, affect recovery of neurons after injury and mitochondria are involved in the regulation of the innate immune response to inflammation. This review article will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after hypoxic-ischemic injury, as a means of identifying new avenues for clinical intervention.
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| 10. |
- Mallard, Carina, 1963, et al.
(författare)
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Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth
- 2014
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Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 75:1, s. 234-240
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Forskningsöversikt (refereegranskat)abstract
- Cerebral palsy is one of the most devastating consequences of brain injury around the time of birth, and nearly a third of cases are now associated with premature birth. Compared with term babies, preterm babies have an increased incidence of complications that may increase the risk of disability, such as intraventricular hemorrhage, periventricular leukomalacia, sepsis, and necrotizing enterocolitis. The response to injury is highly dependent on brain maturity, and although cellular vulnerability is well documented, there is now evidence that premyelinating axons are also particularly sensitive to ischemic injury. In this review, we will explore recent evidence highlighting a central role for glia in mediating increased risk of disability in premature infants, including excessive activation of microglia and opening of astrocytic gap junction hemichannels in spreading injury after brain ischemia, in part likely involving release of adenosine triphosphate (ATP) and overactivation of purinergic receptors, particularly in white matter. We propose the hypothesis that inflammation-induced opening of connexin hemichannels is a key regulating event that initiates a vicious circle of excessive ATP release, which in turn propagates activation of purinergic receptors on microglia and astrocytes. This suggests that developing effective neuroprotective strategies for preterm infants requires a detailed understanding of glial responses.
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