| 1. |
- Baburamani, Ana A, et al.
(författare)
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Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury.
- 2015
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 16:9, s. 22509-26
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Tidskriftsartikel (refereegranskat)abstract
- Perturbation of mitochondrial function and subsequent induction of cell death pathways are key hallmarks in neonatal hypoxic-ischemic (HI) injury, both in animal models and in term infants. Mitoprotective therapies therefore offer a new avenue for intervention for the babies who suffer life-long disabilities as a result of birth asphyxia. Here we show that after oxygen-glucose deprivation in primary neurons or in a mouse model of HI, mitochondrial protein homeostasis is altered, manifesting as a change in mitochondrial morphology and functional impairment. Furthermore we find that the mitochondrial fusion and cristae regulatory protein, OPA1, is aberrantly cleaved to shorter forms. OPA1 cleavage is normally regulated by a balanced action of the proteases Yme1L and Oma1. However, in primary neurons or after HI in vivo, protein expression of YmelL is also reduced, whereas no change is observed in Oma1 expression. Our data strongly suggest that alterations in mitochondria-shaping proteins are an early event in the pathogenesis of neonatal HI injury.
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| 2. |
- Chhor, Vibol, et al.
(författare)
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Role of microglia in a mouse model of paediatric traumatic brain injury.
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 63, s. 197-209
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Tidskriftsartikel (refereegranskat)abstract
- The cognitive and behavioural deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than TBI in the mature brain. Understanding this developmental sensitivity is critical as children under four years of age sustain TBI more frequently than any other age group. Microglia (MG), resident immune cells of the brain that mediate neuroinflammation, are activated following TBI in the immature brain. However, the type and temporal profile of this activation and the consequences of altering it are still largely unknown. In a mouse model of closed head weight drop paediatric brain trauma, we characterized i) the temporal course of total cortical neuroinflammation and the phenotype of ex vivo isolated CD11B-positive microglia/macrophage (MG/MΦ) using a battery of 32 markers, and ii) neuropathological outcome 1 and 5days post-injury. We also assessed the effects of targeting MG/MΦ activation directly, using minocycline a prototypical microglial activation antagonist, on these processes and outcome. TBI induced a moderate increase in both pro- and anti-inflammatory cytokines/chemokines in the ipsilateral hemisphere. Isolated cortical MG/MΦ expressed increased levels of markers of endogenous reparatory/regenerative and immunomodulatory phenotypes compared with shams. Blocking MG/MΦ activation with minocycline at the time of injury and 1 and 2days post-injury had only transient protective effects, reducing ventricular dilatation and cell death 1day post-injury but having no effect on injury severity at 5days. This study demonstrates that, unlike in adults, the role of MG/MΦ in injury mechanisms following TBI in the immature brain may not be negative. An improved understanding of MG/MΦ function in paediatric TBI could support translational efforts to design therapeutic interventions.
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| 3. |
- Erkenstam, Nina Hellström, 1976, et al.
(författare)
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Temporal Characterization of Microglia/Macrophage Phenotypes in a Mouse Model of Neonatal Hypoxic-Ischemic Brain Injury.
- 2016
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Ingår i: Frontiers in cellular neuroscience. - : Frontiers Media SA. - 1662-5102. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Immune cells display a high degree of phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with classical and alternative polarization phenotypes described for macrophages and to identify related cell populations in the brain following neonatal hypoxia-ischemia (HI). HI was induced in 9-day old mice and brain tissue was collected up to 7 days post-insult to investigate expression of genes associated with macrophage activation. Using cell-markers, CD86 (classic activation) and CD206 (alternative activation), we assessed temporal changes of CD11b(+) cell populations in the brain and studied the protein expression of the immunomodulatory factor galectin-3 in these cells. HI induced a rapid regulation (6 h) of genes associated with both classical and alternative polarization phenotypes in the injured hemisphere. FACS analysis showed a marked increase in the number of CD11b(+)CD86(+) cells at 24 h after HI (+3667%), which was coupled with a relative suppression of CD11b(+)CD206(+) cells and cells that did not express neither CD86 nor CD206. The CD11b(+)CD206(+) population was mixed with some cells also expressing CD86. Confocal microscopy confirmed that a subset of cells expressed both CD86 and CD206, particularly in injured gray and white matter. Protein concentration of galectin-3 was markedly increased mainly in the cell population lacking CD86 or CD206 in the injured hemisphere. These cells were predominantly resident microglia as very few galectin-3 positive cells co-localized with infiltrating myeloid cells in Lys-EGFP-ki mice after HI. In summary, HI was characterized by an early mixed gene response, but with a large expansion of mainly the CD86 positive population during the first day. However, the injured hemisphere also contained a subset of cells expressing both CD86 and CD206 and a large population that expressed neither activation marker CD86 nor CD206. Interestingly, these cells expressed the highest levels of galectin-3 and were found to be predominantly resident microglia. Galectin-3 is a protein involved in chemotaxis and macrophage polarization suggesting a novel role in cell infiltration and immunomodulation for this cell population after neonatal injury.
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| 4. |
- Fleiss, Bobbi, et al.
(författare)
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Inflammation-induced sensitization of the brain in term infants.
- 2015
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Ingår i: Developmental medicine and child neurology. - : Wiley. - 1469-8749 .- 0012-1622. ; 57 Suppl 3, s. 17-28
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal 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.
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| 5. |
- Fleiss, Bobbi, et al.
(författare)
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The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia.
- 2015
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Ingår i: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 37:(4-5), s. 363-75
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Tidskriftsartikel (refereegranskat)abstract
- 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. © 2015 S. Karger AG, Basel.
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| 6. |
- 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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| 7. |
- Koning, Gabriella, et al.
(författare)
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Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection.
- 2019
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - 1559-7016. ; 39:6, s. 1038-1055
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Tidskriftsartikel (refereegranskat)abstract
- Magnesium sulphate (MgSO4) given to women in preterm labor reduces cerebral palsy in their offspring but the mechanism behind this protection is unclear, limiting its effective, safe clinical implementation. Previous studies suggest that MgSO4 is not neuroprotective if administered during or after the insult, so we hypothesised that MgSO4 induces preconditioning in the immature brain. Therefore, we administered MgSO4 at various time-points before/after unilateral hypoxia-ischemia (HI) in seven-day-old rats. We found that MgSO4 treatment administered as a bolus between 6 days and 12h prior to HI markedly reduced the brain injury, with maximal protection achieved by 1.1mg/g MgSO4 administered 24h before HI. As serum magnesium levels returned to baseline before the induction of HI, we ascribed this reduction in brain injury to preconditioning. Cerebral blood flow was unaffected, but mRNAs/miRNAs involved in mitochondrial function and metabolism were modulated by MgSO4. Metabolomic analysis (H+-NMR) disclosed that MgSO4 attenuated HI-induced increases in succinate and prevented depletion of high-energy phosphates. MgSO4 pretreatment preserved mitochondrial respiration, reducing ROS production and inflammation after HI. Therefore, we propose that MgSO4 evokes preconditioning via induction of mitochondrial resistance and attenuation of inflammation.
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| 8. |
- Koning, Gabriella, et al.
(författare)
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Magnesium sulphate induces preconditioning in preterm rodent models of cerebral hypoxia-ischemia.
- 2018
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Ingår i: International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. - : Wiley. - 1873-474X. ; 70, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- Brain injury in preterm infants represents a substantial clinical problem associated with development of motor impairment, cognitive deficits and psychiatric problems. According to clinical studies, magnesium sulphate (MgSO4) given to women in preterm labor reduces the risk of cerebral palsy in the offspring but the mechanisms behind its neuroprotective effects are still unclear. Our aim was to explore whether MgSO4 induces tolerance (preconditioning) in the preterm rodent brain. For this purpose we established a model of perinatal hypoxia-ischemia (HI) in postnatal day 4 rats and also applied a recently developed postnatal day 5 mouse model of perinatal brain injury.Postnatal day 4 Wistar rats were exposed to unilateral carotid artery ligation followed by 60, 70 or 80min of hypoxia (8% O2). On postnatal day 11, brains were collected and macroscopically visible damage as well as white and grey matter injury was examined using immunohistochemical staining. Once the model had been established, a possible preconditioning protection induced by a bolus MgSO4 injection prior to 80min HI was examined 7days after the insult. Next, a MgSO4 bolus was injected in C57Bl6 mice on PND 4 followed by exposure to unilateral carotid artery ligation and hypoxia, (10% O2) for 70min on PND 5. Brains were collected 7days after the insult and examined with immunohistochemistry for grey and white matter injury.In rats, a 60min period of hypoxia resulted in very few animals with brain injury and although 70min of hypoxia resulted in a higher percentage of injured animals, the brains were marginally damaged. An 80min exposure of hypoxia caused cortical tissue damage combined with hippocampal atrophy and neuronal loss in the C3 hippocampal layer. In the rat model, MgSO4 (1.1mg/g administered i.p. 24h prior to the induction of HI, resulting in a transient serum Mg2+ concentration elevation to 4.1±0.2mmol/l at 3h post i.p. injection) reduced brain injury by 74% in grey matter and 64% in white matter. In the mouse model, MgSO4 (0.92mg/g) i.p. injection given 24h prior to the HI insult resulted in a Mg2+ serum concentration increase reaching 2.7±0.3mmol/l at 3h post injection, which conferred a 40% reduction in grey matter injury.We have established a postnatal day 4 rat model of HI for the study of preterm brain injury. MgSO4 provides a marked preconditioning protection both in postnatal day 4 rats and in postnatal day 5 mice.
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| 9. |
- Rangon, Claire-Marie, et al.
(författare)
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Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury.
- 2018
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 74, s. 265-276
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Tidskriftsartikel (refereegranskat)abstract
- Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1β (IL-1β) injections. We initiated GSK247246 treatment (i.p at 7mg/kg or 20mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI.
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| 10. |
- Van Steenwinckel, Juliette, et al.
(författare)
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Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain.
- 2019
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 142:12, s. 3806-3833
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Tidskriftsartikel (refereegranskat)abstract
- Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.
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