| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
- 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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| 4. |
- Fazey, Ioan, et al.
(författare)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
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Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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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. |
- Furberg, Helena, et al.
(författare)
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Genome-wide meta-analyses identify multiple loci associated with smoking behavior
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 134-441
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Tidskriftsartikel (refereegranskat)abstract
- Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
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| 7. |
- Hagberg, Henrik, 1955, et al.
(författare)
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Mitochondria: hub of injury responses in the developing brain.
- 2014
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Ingår i: Lancet neurology. - 1474-4465. ; 13:2, s. 217-32
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Tidskriftsartikel (refereegranskat)abstract
- Progress in the field of mitochondrial biology in the past few years has shown that mitochondrial activities go beyond bioenergetics. These new aspects of mitochondrial physiology and pathophysiology have important implications for the immature brain. A picture emerges in which mitochondrial biogenesis, mitophagy, migration, and morphogenesis are crucial for brain development and synaptic pruning, and play a part in recovery after acute insults. Mitochondria also affect brain susceptibility to injury, and mitochondria-directed interventions can make the immature brain highly resistant to acute injury. Finally, the mitochondrion is a platform for innate immunity, contributes to inflammation in response to infection and acute damage, and participates in antiviral and antibacterial defence. Understanding of these new aspects of mitochondrial function will provide insights into brain development and neurological disease, and enable discovery and development of new strategies for treatment.
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| 8. |
- Järlestedt, Katarina, et al.
(författare)
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Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxic-ischemic brain injury.
- 2013
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - Bethesda : Wiley. - 1530-6860 .- 0892-6638. ; 27:9, s. 3797-3804
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Tidskriftsartikel (refereegranskat)abstract
- Complement is an essential component of inflammation that plays a role in ischemic brain injury. Recent reports demonstrate novel functions of complement in normal and diseased CNS, such as regulation of neurogenesis and synapse elimination. Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI-induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy.-Järlestedt, K., Rousset, C. I., Ståhlberg, A., Sourkova, H., Atkins, A. L., Thornton, C., Barnum, S. R., Wetsel, R. A., Dragunow, M., Pekny, M., Mallard, C., Hagberg, H., Pekna, M. Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxic-ischemic brain injury.
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| 9. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 10. |
- Kichev, Anton, et al.
(författare)
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TNF-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation.
- 2014
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Ingår i: The Journal of biological chemistry. - 1083-351X. ; 289:13, s. 9430-39
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Tidskriftsartikel (refereegranskat)abstract
- Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) is a member of the TNF family. The interaction of TRAIL with death receptor 4 (DR4) and DR5 can trigger apoptotic cell death. The aim of this study was to investigate the role of TRAIL signaling in neonatal hypoxia-ischemia (HI). Using a neonatal mouse model of HI, mRNA and protein expression of TRAIL, DR5 and the TRAIL decoy receptors osteoprotegerin (OPG), mDcTRAILR1 and mDcTRAILR2 were determined. In vitro, mRNA expression of these genes was measured in primary neurons and oligodendrocyte progenitor cells (OPCs) after inflammatory cytokine (TNF-α/IFN-γ) treatment and/or oxygen and glucose deprivation (OGD). The toxicity of these various paradigms was also measured. The expression of TRAIL, DR5, OPG and mDcTRAILR2 was significantly increased after HI. In vitro, inflammatory cytokines and OGD treatment significantly induced mRNAs for TRAIL, DR5, OPG and mDcTRAILR2 in primary neurons, and of TRAIL and OPG in OPCs. TRAIL protein was expressed primarily in microglia and astroglia whereas DR5 co-localized with neurons and OPCs in vivo. OGD enhanced TNF-α/IFN-γ toxicity in both neuronal and OPC cultures. Recombinant TRAIL exerted toxicity alone or in combination with OGD and TNF-α/IFN-γ in primary neurons but not in OPC cultures. The marked increases in the expression of TRAIL and its receptors after cytokine exposure and OGD in primary neurons and OPCs were similar to those found in our animal model of neonatal HI. The toxicity of TRAIL in primary neurons suggests that TRAIL signaling participates in neonatal brain injury after inflammation and HI.
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| 11. |
- 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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| 12. |
- 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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| 13. |
- Mylrea-Foley, Bronacha, et al.
(författare)
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Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise : the TRUFFLE 2 randomised trial protocol
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years.Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (>= 4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire.Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy.
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| 14. |
- Nair, Syam, et al.
(författare)
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Death associated protein kinases: molecular structure and brain injury.
- 2013
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 14:7, s. 13858-72
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk) family, DAPk1, has been implicated in cerebral ischemic damage, whereby DAPk1 potentiates NMDA receptor-mediated excitotoxicity through interaction with the NR2BR subunit. DAPk1 also mediate a range of activities from autophagy, membrane blebbing and DNA fragmentation ultimately leading to cell death. DAPk mRNA levels are particularly highly expressed in the developing brain and thus, we hypothesize that DAPk1 may play a role in perinatal brain injury. In addition to reviewing current knowledge, we present new aspects of the molecular structure of DAPk domains, and relate these findings to interacting partners of DAPk1, DAPk-regulation in NMDA-induced cerebral injury and novel approaches to blocking the injurious effects of DAPk1.
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| 15. |
- Nezhyva, Mariya, et al.
(författare)
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Spatial multiomic insights into acute cocaine exposure
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Recent studies provide compelling evidence that cocaine-induced neurotoxicity begins within hours of a single acute cocaine exposure. Despite this, a comprehensive understanding of the molecular alterations occurring in vivo within the reward system following such an exposure has been lacking. In this study, we developed an analytical workflow that combines mass spectrometry imaging with microscale proteomics of brain regions. Here, we present a multiomic perspective on the molecular consequences of acute cocaine exposure on the principal areas of the reward system and the hippocampus. Our findings include distinct region-specific alterations in the tricarboxylic acid (TCA) cycle and lipid synthesis within the reward circuitry highlighting a significant energy depletion in mice 24 hours post-cocaine injections. Additionally, we linked widespread reductions in key neurotransmitters (GABA, glutamate, aspartate) across the reward system and calcium level modifications to changes in synaptic plasticity and mitochondria dysfunction. Mitochondrial dysfunction and energy metabolism disruption were evident through imbalances in the mitochondrial ATP production and electron transport chain components, increased susceptibility to oxidative stress, disturbances in mitochondrial transport proteins, and fluctuations in creatine and taurine levels. Among the brain regions within the reward circuitry, the prefrontal cortex (PFC) exhibited the most pronounced effects. This study not only provides a holistic overview of the intricate interplay between proteins and metabolites within the reward circuitry regions during the onset of cocaine-induced neurotoxicity but also offers novel insights into the underlying molecular mechanisms.
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| 16. |
- Poupon-Bejuit, Laura, et al.
(författare)
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Diabetes drugs activate neuroprotective pathways in models of neonatal hypoxic-ischemic encephalopathy
- 2024
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Ingår i: EMBO MOLECULAR MEDICINE. - 1757-4676 .- 1757-4684. ; 16:6, s. 1284-1309
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischaemic encephalopathy (HIE) arises from diminished blood flow and oxygen to the neonatal brain during labor, leading to infant mortality or severe brain damage, with a global incidence of 1.5 per 1000 live births. Glucagon-like Peptide 1 Receptor (GLP1-R) agonists, used in type 2 diabetes treatment, exhibit neuroprotective effects in various brain injury models, including HIE. In this study, we observed enhanced neurological outcomes in post-natal day 10 mice with surgically induced hypoxic-ischaemic (HI) brain injury after immediate systemic administration of exendin-4 or semaglutide. Short- and long-term assessments revealed improved neuropathology, survival rates, and locomotor function. We explored the mechanisms by which GLP1-R agonists trigger neuroprotection and reduce inflammation following oxygen-glucose deprivation and HI in neonatal mice, highlighting the upregulation of the PI3/AKT signalling pathway and increased cAMP levels. These findings shed light on the neuroprotective and anti-inflammatory effects of GLP1-R agonists in HIE, potentially extending to other neurological conditions, supporting their potential clinical use in treating infants with HIE. Hypoxic-ischaemic encephalopathy (HIE) is caused by complications during labor or the umbilical cord causing reduced oxygen to the baby's brain. This leads to brain injury and lifelong disability or death. Administration of GLP1 receptor agonists to a mouse model of HIE reduces brain damage and improves multiple readouts of efficacy.A single peripheral administration of a GLP1 receptor agonist, used in the clinic to treat diabetes, significantly reduced brain infarct size and improved survival and locomotor function in a mouse model of neonatal HIE. GLP1 receptor agonists activated neuroprotective pathways and reduced markers of inflammatory response in the brain. This study is supportive of further investigating the clinical application of GLP1 receptor agonist for HIE but also more widely for other neurological diseases. Hypoxic-ischaemic encephalopathy (HIE) is caused by complications during labor or the umbilical cord causing reduced oxygen to the baby's brain. This leads to brain injury and lifelong disability or death. Administration of GLP1 receptor agonists to a mouse model of HIE reduces brain damage and improves multiple readouts of efficacy.
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| 17. |
- Poupon-Bejuit, Laura, et al.
(författare)
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Neuroprotective Effects of Diabetes Drugs for the Treatment of Neonatal Hypoxia-Ischemia Encephalopathy.
- 2020
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Ingår i: Frontiers in cellular neuroscience. - : Frontiers Media SA. - 1662-5102. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- The perinatal period represents a time of great vulnerability for the developing brain. A variety of injuries can result in death or devastating injury causing profound neurocognitive deficits. Hypoxic-ischemic neonatal encephalopathy (HIE) remains the leading cause of brain injury in term infants during the perinatal period with limited options available to aid in recovery. It can result in long-term devastating consequences with neurologic complications varying from mild behavioral deficits to severe seizure, intellectual disability, and/or cerebral palsy in the newborn. Despite medical advances, the only viable option is therapeutic hypothermia which is classified as the gold standard but is not used, or may not be as effective in preterm cases, infection-associated cases or low resource settings. Therefore, alternatives or adjunct therapies are urgently needed. Ongoing research continues to advance our understanding of the mechanisms contributing to perinatal brain injury and identify new targets and treatments. Drugs used for the treatment of patients with type 2 diabetes mellitus (T2DM) have demonstrated neuroprotective properties and therapeutic efficacy from neurological sequelae following HIE insults in preclinical models, both alone, or in combination with induced hypothermia. In this short review, we have focused on recent findings on the use of diabetes drugs that provide a neuroprotective effect using in vitro and in vivo models of HIE that could be considered for clinical translation as a promising treatment.
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| 18. |
- Rousset, Catherine I, et al.
(författare)
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Mitochondria and perinatal brain injury.
- 2012
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Ingår i: The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. - : Informa UK Limited. - 1476-4954. ; 25 Suppl 1, s. 35-8
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Tidskriftsartikel (refereegranskat)abstract
- Secondary brain injury after hypoxia-ischemia is associated with delayed loss of high energy phosphates implicating bioenergetic mitochondrial failure at least partly related to deregulation of the energy sensor adenosine monophosphate-activated protein kinase. Furthermore, the toxic intracellular environment (accumulation of reactive oxygen/nitrosative species and intracellular calcium) during post-ischemic reperfusion triggers Bax-dependent mitochondrial permeabilization (MP) leading to activation of caspase-dependent and apoptosis-inducing factor dependent cell death. We still do not understand how MP is induced but some data suggest that mitochondrial fusion/fission as well as migration play a critical role. Mitochondrial dynamics also seem critical for brain development as genetic deficiency of proteins involved in mitochondrial fusion and fission results in malformations including microcephaly, abnormal brain development and dysmyelination. In this brief review, we update the critical role of mitochondria in brain development and the decision of cell fate after hypoxia-ischemia in the immature CNS.
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| 19. |
- Thornton, Claire, et al.
(författare)
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Mitochondrial dynamics, mitophagy and biogenesis in neonatal hypoxic-ischaemic brain injury
- 2018
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793. ; 592:5, s. 812-830
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Forskningsöversikt (refereegranskat)abstract
- Hypoxic-ischaemic encephalopathy, resulting from asphyxia during birth, affects 2-3 in every 1000 term infants and depending on severity, brings about life-changing neurological consequences or death. This hypoxic-ischaemia (HI) results in a delayed neural energy failure during which the majority of brain injury occurs. Currently, there are limited treatment options and additional therapies are urgently required. Mitochondrial dysfunction acts as a focal point in injury development in the immature brain. Not only do mitochondria become permeabilised, but recent findings implicate perturbations in mitochondrial dynamics (fission, fusion), mitophagy and biogenesis. Mitoprotective therapies may therefore offer a new avenue of intervention for babies who suffer lifelong disabilities due to birth asphyxia.
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| 20. |
- 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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| 21. |
- Thornton, Claire, et al.
(författare)
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Role of mitochondria in apoptotic and necroptotic cell death in the developing brain.
- 2015
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Ingår i: Clinica chimica acta; international journal of clinical chemistry. - : Elsevier BV. - 1873-3492. ; 451:Part: A Special Issue: SI, s. 35-38
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischemic encephalopathy induces secondary brain injury characterized by delayed energy failure. Currently, therapeutic hypothermia is the sole treatment available after severe intrapartum asphyxia in babies and acts to attenuate secondary loss of high energy phosphates improving both short- and long-term outcome. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. Hypoxia-ischemia creates a toxic intracellular environment including accumulation of reactive oxygen/nitrosative species and intracellular calcium after the insult, inducing mitochondrial impairment. More specifically mitochondrial respiration is suppressed and calcium signaling is dysregulated. At a certain threshold, Bax-dependent mitochondrial permeabilization will occur leading to activation of caspase-dependent and apoptosis-inducing factor-dependent apoptotic cell death. In addition, hypoxia-ischemia induces inflammation, which leads to the release of TNF-α, TRAIL, TWEAK, FasL and Toll-like receptor agonists that will activate death receptors on neurons and oligodendroglia. Death receptors trigger apoptotic death via caspase-8 and necroptotic cell death through formation of the necrosome (composed of RIP1, RIP3 and MLKL), both of which converge at the mitochondria.
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| 22. |
- Vontell, Regina, et al.
(författare)
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Cellular mechanisms of toll-like receptor-3 activation in the thalamus are associated with white matter injury in the developing brain.
- 2015
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Ingår i: Journal of neuropathology and experimental neurology. - 1554-6578. ; 74:3, s. 273-85
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptor-3 (TLR3) has been identified in a variety of intracellular structures (e.g. endosomes and endoplasmic reticulum); it detects viral molecular patterns and damage-associated molecular patterns. We hypothesized that, after white matter injury (WMI) has occurred, localization and activation of TLR3 are altered in gray matter structures in response to damage-associated molecular patterns and activated glia. Therefore, we investigated the subcellular localization of TLR3 and its downstream signaling pathway in postmortem brain sections from preterm infants with and without WMI (7 patients each). We assessed astroglia (glial fibrillary acidic protein-positive), microglia (ionized calcium-binding adaptor molecule-1-positive), and neuronal populations in 3 regions of the thalamus and in the posterior limb of the internal capsule and analyzed TLR3 messenger RNA and protein expression in the ventral lateral posterior thalamic region, an area associated with impaired motor function. We also assessed TLR3 colocalization with late endosomes (lysosome-associated membrane protein-1) and phagosomal compartments in this region. Glial fibrillary acidic protein, ionized calcium-binding adaptor molecule-1, and TLR3 immunoreactivity and messenger RNA expression were increased in cases with WMI compared with controls. In ventral lateral posterior neurons, TLR3 was colocalized with the endoplasmic reticulum and the autophagosome, suggesting that autophagy may be a stress response associated with WMI. Thus, alterations in TLR3 expression in WMI may be an underlying molecular mechanism associated with impaired development in preterm infants.
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| 23. |
- Zhang, Xiaoli, et al.
(författare)
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γδT cells but not αβT cells contribute to sepsis-induced white matter injury and motor abnormalities in mice
- 2017
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Infection and sepsis are associated with brain white matter injury in preterm infants and the subsequent development of cerebral palsy. Methods In the present study, we used a neonatal mouse sepsis-induced white matter injury model to determine the contribution of different T cell subsets (αβT cells and γδT cells) to white matter injury and consequent behavioral changes. C57BL/6J wild-type (WT), T cell receptor (TCR) δ-deficient (Tcrd −/−, lacking γδT cells), and TCRα-deficient (Tcra −/−, lacking αβT cells) mice were administered with lipopolysaccharide (LPS) at postnatal day (PND) 2. Brain myelination was examined at PNDs 12, 26, and 60. Motor function and anxiety-like behavior were evaluated at PND 26 or 30 using DigiGait analysis and an elevated plus maze. Results White matter development was normal in Tcrd −/− and Tcrα −/− compared to WT mice. LPS exposure induced reductions in white matter tissue volume in WT and Tcrα −/− mice, but not in the Tcrd −/− mice, compared with the saline-treated groups. Neither LPS administration nor the T cell deficiency affected anxiety behavior in these mice as determined with the elevated plus maze. DigiGait analysis revealed motor function deficiency after LPS-induced sepsis in both WT and Tcrα −/− mice, but no such effect was observed in Tcrd −/− mice. Conclusions Our results suggest that γδT cells but not αβT cells contribute to sepsis-induced white matter injury and subsequent motor function abnormalities in early life. Modulating the activity of γδT cells in the early stages of preterm white matter injury might represent a novel therapeutic strategy for the treatment of perinatal brain injury.
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