| 1. |
- Chhor, Vibol, et al.
(författare)
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Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro.
- 2013
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 32, s. 70-85
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Tidskriftsartikel (refereegranskat)abstract
- Microglia mediate multiple facets of neuroinflammation, including cytotoxicity, repair, regeneration, and immunosuppression due to their ability to acquire diverse activation states, or phenotypes. Modulation of microglial phenotype is an appealing neurotherapeutic strategy but a comprehensive study of classical and more novel microglial phenotypic markers in vitro is lacking. The aim of this study was to outline the temporal expression of a battery of phenotype markers from polarised microglia to generate an in vitro tool for screening the immunomodulatory potential of novel compounds. We characterised expression of thirty-one macrophage/microglial phenotype markers in primary microglia over time (4, 12, 36, and 72h), using RT-qPCR or multiplex protein assay. Firstly, we selected Interleukin-4 (IL-4) and lipopolysaccharide (LPS) as the strongest M1-M2 polarising stimuli, from six stimuli tested. At each time point, markers useful to identify that microglia were M1 included iNOS, Cox-2 and IL-6 and a loss of M2a markers. Markers useful for quantifying M2b-immunomodulatory microglia included, increased IL-1RA and SOCS3 and for M2a-repair and regeneration, included increased arginase-1, and a loss of the M1 and M2b markers were discriminatory. Additional markers were regulated at fewer time points, but are still likely important to monitor when assessing the immunomodulatory potential of novel therapies. Further, to facilitate identification of how novel immunomodulatory treatments alter the functional affects of microglia, we characterised how the soluble products from polarised microglia affected the type and rate of neuronal death; M1/2b induced increasing and M2a-induced decreasing neuronal loss. We also assessed any effects of prior activation state, to provide a way to identify how a novel compound may alter phenotype depending on the stage of injury/insult progression. We identified generally that a prior M1/2b reduced the ability of microglia to switch to M2a. Altogether, we have characterised a profile of phenotype markers and a mechanism of assessing functional outcome that we can use as a reference guide for first-line screening of novel immunomodulatory therapies in vitro in the search for viable neuroprotectants.
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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. |
- Dean, J., et al.
(författare)
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Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro
- 2010
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Ingår i: Brain, Behavior, and Immunity. - : Elsevier BV. - 0889-1591. ; 24:5, s. 776-83
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Tidskriftsartikel (refereegranskat)abstract
- Although the role of microglial activation in neural injury remains controversial, there is increasing evidence for a detrimental effect in the immature brain, which may occur in response to release of neurotoxic substances including pro-inflammatory cytokines. However, the signaling mechanisms involved in microglial-induced neuronal cell death are unclear. Microglia isolated from the brains of wild-type (WT) or MyD88 knockout (KO) mice were exposed to PBS or the TLR4-ligand LPS (100 ng/mL) for 2, 6, 14, or 24 h, and the microglia-conditioned medium (MCM) collected. Detection of multiple inflammatory molecules in MCM was performed using a mouse 22-plex cytokine microbead array kit. Primary neuronal cultures were supplemented with the 14 h or 24 h MCM, and the degree of neuronal apoptosis examined after exposure for 24 h. Results showed a rapid and sustained elevation in multiple inflammatory mediators in the MCM of WT microglia exposed to LPS, which was largely inhibited in MyD88 KO microglia. There was a significant increase in apoptotic death measured at 24 h in cultured neurons exposed to CM from either 14 h or 24 h LPS-stimulated WT microglia (p < .05 vs. WT control). By contrast, there was no increase in apoptotic death in cultured neurons exposed to CM from 14 h or 24 h LPS-stimulated MyD88 KO microglia (p = .15 vs. MyD88 KO control). These data suggest that MyD88-dependent activation of microglia by LPS causes release of factors directly toxic to neurons.
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| 4. |
- Du, Xiaonan, et al.
(författare)
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Systemic stimulation of TLR2 impairs neonatal mouse brain development.
- 2011
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is associated with perinatal brain injury but the underlying mechanisms are not completely characterized. Stimulation of Toll-like receptors (TLRs) through specific agonists induces inflammatory responses that trigger both innate and adaptive immune responses. The impact of engagement of TLR2 signaling pathways on the neonatal brain is still unclear. The aim of this study was to investigate the potential effect of a TLR2 agonist on neonatal brain development.
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| 5. |
- 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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| 6. |
- Favrais, Géraldine, et al.
(författare)
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Systemic inflammation disrupts the developmental program of white matter.
- 2011
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:4, s. 550-565
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Perinatal inflammation is a major risk factor for neurological deficits in preterm infants. Several experimental studies have shown that systemic inflammation can alter the programming of the developing brain. However, these studies do not offer detailed pathophysiological mechanisms, and they rely on relatively severe infectious or inflammatory stimuli that most likely do not reflect the levels of systemic inflammation observed in many human preterm infants. The goal of the present study was to test the hypothesis that moderate systemic inflammation is sufficient to alter white matter development. METHODS: Newborn mice received twice-daily intraperitoneal injections of interleukin-1β (IL-1β) over 5 days and were studied for myelination, oligodendrogenesis, and behavior and with magnetic resonance imaging (MRI). RESULTS: Mice exposed to IL-1β had a long-lasting myelination defect that was characterized by an increased number of nonmyelinated axons. They also displayed a reduction of the diameter of the myelinated axons. In addition, IL-1β induced a significant reduction of the density of myelinating oligodendrocytes accompanied by an increased density of oligodendrocyte progenitors, suggesting a partial blockade in the oligodendrocyte maturation process. Accordingly, IL-1β disrupted the coordinated expression of several transcription factors known to control oligodendrocyte maturation. These cellular and molecular abnormalities were correlated with a reduced white matter fractional anisotropy on diffusion tensor imaging and with memory deficits. INTERPRETATION: Moderate perinatal systemic inflammation alters the developmental program of the white matter. This insult induces a long-lasting myelination deficit accompanied by cognitive defects and MRI abnormalities, further supporting the clinical relevance of the present data. ANN NEUROL 2011.
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| 7. |
- 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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| 8. |
- Fleiss, Bobbi, et al.
(författare)
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Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury.
- 2012
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Ingår i: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Perinatal brain injury is complex and often associated with both inflammation and hypoxia-ischaemia (HI). In adult inflammatory brain injury models, therapies to increase acetylation are efficacious in reducing inflammation and cerebral injury. Our aim in the present study was to examine the neuropathological and functional effects of the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) in a model of neonatal lipopolysaccharide (LPS)-sensitised HI. We hypothesised that, by decreasing inflammation, TSA would improve injury and behavioural outcome. Furthermore, TSA's effects on oligodendrocyte development, which is acetylation-dependent, were investigated. METHODS: On postnatal day 8 (P8), male and female mice were exposed to LPS together with or without TSA. On P9 (14 hours after LPS), mice were exposed to HI (50 minutes at 10% O2). Neuropathology was assessed at 24 hours, 5 days and 27 days post-LPS/HI via immunohistochemistry and/or Western blot analysis for markers of grey matter (microtubule-associated protein 2), white matter (myelin basic protein) and cell death (activated caspase-3). Effects of TSA on LPS or LPS/HI-induced inflammation (cytokines and microglia number) were assessed by Luminex assay and immunohistochemistry. Expression of acetylation-dependent oligodendrocyte maturational corepressors was assessed with quantitative PCR 6 hours after LPS and at 24 hours and 27 days post-LPS/HI. Animal behaviour was monitored with the open-field and trace fear-conditioning paradigms at 25 days post-LPS/HI to identify functional implications of changes in neuropathology associated with TSA treatment. RESULTS: TSA increased acetylation in females after LPS exposure, but not in males. Also only in females, TSA reduced grey matter and white matter injury at 5 days post-LPS/HI. TSA treatment altered animal behaviour in the open field and improved learning in the fear-conditioning test in females compared with LPS/HI only females at 25 days post-HI. None of the inflammatory mechanisms assessed that are known to mediate neuroprotection by HDACi in adults correlated with improved outcome in TSA-treated neonatal females. Oligodendrocyte maturation was not different between the LPS-only and LPS + TSA-treated mice before or after exposure to HI. CONCLUSIONS: Hyperacetylation with TSA is neuroprotective in the female neonatal mouse following LPS/HI and correlates with improved learning long-term. TSA appears to exert neuroprotection via mechanisms unique to the neonate. Deciphering the effects of age, sex and inflammatory sensitisation in the cerebral response to HDACi is key to furthering the potential of hyperacetylation as a viable neuroprotectant. TSA did not impair oligodendrocyte maturation, which increases the possible clinical relevance of this strategy.
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| 9. |
- Fleiss, Bobbi, et al.
(författare)
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Stem Cell Therapy for Neonatal Brain Injury.
- 2014
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Ingår i: Clinics in perinatology. - : Elsevier BV. - 1557-9840 .- 0095-5108. ; 41:1, s. 133-148
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Tidskriftsartikel (refereegranskat)abstract
- This article introduces the basic concepts of modeling neonatal brain injury and provides background information regarding each of the commonly used types of stem cells. It summarizes the findings of preclinical research testing the therapeutic potential of stem cells in animal models of neonatal brain injury, reports briefly on the status of clinical trials, and discusses the important ongoing issues that need to be addressed before stem cell therapy is used to repair the injured brain.
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| 10. |
- 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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| 11. |
- Lingam, Ingran, et al.
(författare)
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Serial blood cytokine and chemokine mRNA and microRNA over 48h are insult specific in a piglet model of inflammation-sensitized hypoxia-ischaemia.
- 2021
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Ingår i: Pediatric research. - : Springer Science and Business Media LLC. - 1530-0447 .- 0031-3998. ; 89:3, s. 464-475
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to inflammation exacerbates injury in neonatal encephalopathy (NE). We hypothesized that brain biomarker mRNA, cytokine mRNA and microRNA differentiate inflammation (E. coli LPS), hypoxia (Hypoxia), and inflammation-sensitized hypoxia (LPS+Hypoxia) in an NE piglet model.Sixteen piglets were randomized: (i) LPS 2μg/kg bolus; 1μg/kg infusion (LPS; n=5), (ii) Saline with hypoxia (Hypoxia; n=6), (iii) LPS commencing 4h pre-hypoxia (LPS+Hypoxia; n=5). Total RNA was acquired at baseline, 4h after LPS and 1, 3, 6, 12, 24, 48h post-insult (animals euthanized at 48h). Quantitative PCR was performed for cytokines (IL1A, IL6, CXCL8, IL10, TNFA) and brain biomarkers (ENO2, UCHL1, S100B, GFAP, CRP, BDNF, MAPT). MicroRNA was detected using GeneChip (Affymetrix) microarrays. Fold changes from baseline were compared between groups and correlated with cell death (TUNEL) at 48h.Within 6h post-insult, we observed increased IL1A, CXCL8, CCL2 and ENO2 mRNA in LPS+Hypoxia and LPS compared to Hypoxia. IL10 mRNA differentiated all groups. Four microRNAs differentiated LPS+Hypoxia and Hypoxia: hsa-miR-23a, 27a, 31-5p, 193-5p. Cell death correlated with TNFA (R=0.69; p<0.01) at 1-3h and ENO2 (R=-0.69; p=0.01) at 48h.mRNA and miRNA differentiated hypoxia from inflammation-sensitized hypoxia within 6h in a piglet model. This information may inform human studies to enable triage for tailored neuroprotection in NE.Early stratification of infants with neonatal encephalopathy is key to provide tailored neuroprotection.IL1A, CXCL8, IL10, CCL2 and NSE mRNA are promising biomarkers of inflammation-sensitized hypoxia.IL10 mRNA levels differentiated all three pathological states; fold changes from baseline was the highest in LPS+Hypoxia animals, followed by LPS and Hypoxia at 6h.miR-23, -27, -31-5p and -193-5p were significantly upregulated within 6h of a hypoxia insult.Functional analysis highlighted the diverse roles of miRNA in the cellular processes.
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| 12. |
- Nair, Syam, et al.
(författare)
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Neuroprotection offered by mesenchymal stem cells in perinatal brain injury: Role of mitochondria, inflammation and reactive oxygen species.
- 2021
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 158:1, s. 59-73
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Forskningsöversikt (refereegranskat)abstract
- Preclinical studies have shown that mesenchymal stem cell have a positive effect in perinatal brain injury models. The mechanisms that cause these neurotherapeutic effects are not entirely intelligible. Mitochondrial damage, inflammation and reactive oxygen species are considered to be critically involved in the development of injury. Mesenchymal stem cells have immunomodulatory action and exert mitoprotective effects which attenuate production of reactive oxygen species and promote restoration of tissue function and metabolism after perinatal insults. This review summarizes the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy.
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| 13. |
- 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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| 14. |
- Schang, Anne-Laure, et al.
(författare)
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Failure of thyroid hormone treatment to prevent inflammation-induced white matter injury in the immature brain.
- 2014
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 37, s. 95-102
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth is very strongly associated with maternal/foetal inflammation and leads to permanent neurological deficits. These deficits correlate with the severity of white matter injury, including maturational arrest of oligodendrocytes and hypomyelination. Preterm birth and exposure to inflammation causes hypothyroxinemia. As such, supplementation with thyroxine (T4) seems a good candidate therapy for reducing white matter damage in preterm infants as oligodendrocyte maturation and myelination is regulated by thyroid hormones. We report on a model of preterm inflammation-induced white matter damage, in which induction of systemic inflammation by exposure from P1 to P5 to interleukin-1β (IL-1β) causes oligodendrocyte maturational arrest and hypomyelination. This model identified transient hypothyroidism and wide-ranging dysfunction in thyroid hormone signalling pathways. To test whether a clinically relevant dose of T4 could reduce inflammation-induced white matter damage we concurrently treated mice exposed to IL-1β from P1 to P5 with T4 (20μg/kg/day). At P10, we isolated O4-positive pre-oligodendrocytes and gene expression analysis revealed that T4 treatment did not recover the IL-1β-induced blockade of oligodendrocyte maturation. Moreover, at P10 and P30 immunohistochemistry for markers of oligodendrocyte lineage (NG2, PDGFRα and APC) and myelin (MBP) similarly indicated that T4 treatment did not recover IL-1β-induced deficits in the white matter. In summary, in this model of preterm inflammation-induced white matter injury, a clinical dose of T4 had no therapeutic efficacy. We suggest that additional pre-clinical trials with T4 covering the breadth and scope of causes and outcomes of perinatal brain injury are required before we can correctly evaluate clinical trials data and understand the potential for thyroid hormone as a widely implementable clinical therapy.
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| 15. |
- Thornton, Claire, et al.
(författare)
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Molecular mechanisms of neonatal brain injury.
- 2012
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Ingår i: Neurology research international. - : Hindawi Limited. - 2090-1860 .- 2090-1852. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- Fetal/neonatal brain injury is an important cause of neurological disability. Hypoxia-ischemia and excitotoxicity are considered important insults, and, in spite of their acute nature, brain injury develops over a protracted time period during the primary, secondary, and tertiary phases. The concept that most of the injury develops with a delay after the insult makes it possible to provide effective neuroprotective treatment after the insult. Indeed, hypothermia applied within 6 hours after birth in neonatal encephalopathy reduces neurological disability in clinical trials. In order to develop the next generation of treatment, we need to know more about the pathophysiological mechanism during the secondary and tertiary phases of injury. We review some of the critical molecular events related to mitochondrial dysfunction and apoptosis during the secondary phase and report some recent evidence that intervention may be feasible also days-weeks after the insult.
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| 16. |
- 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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