| 1. |
- Bolouri, Hayde, 1957, et al.
(författare)
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Innate defence regulator peptide 1018 protects against perinatal brain injury.
- 2014
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 75:3, s. 395-410
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Tidskriftsartikel (refereegranskat)abstract
- Objective: There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury, therefore, the neuroprotective therapeutic potential of innate defence regulator peptides (IDRs) was investigated. Methods: The anti-inflammatory effects of three IDRs was measured in LPS-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3h after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 h before LPS or 3h after LPS+HI. Results: IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3h after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for e.g. Fadd and Tnfsf9) and inflammatory (for e.g. IL-1, TNF-α, chemokines and cell adhesion molecules) pathways and showed marked protection of both white and grey brain matter. Interpretation: IDR-1018 supresses pro-inflammatory mediators and cell injurious mechanisms in the developing brain, and post-insult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both grey and white matter, and lacks significant effects on the brain under normal conditions. Thus this peptide provides the features of a promising neuroprotective agent in newborns with brain injury. ANN NEUROL 2013. © 2013 American Neurological Association.
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| 2. |
- Carlsson, Ylva, 1975, et al.
(författare)
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Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury.
- 2011
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:5, s. 781-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Perinatal brain injury is a major cause of neurodevelopmental handicaps. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to cell damage and death, including caspase-dependent apoptosis. Caspase-2 (Casp2; Nedd-2, Ich-1) is a developmentally regulated initiator caspase, which poorly cleaves other caspases but can initiate mitochondrial outer membrane permeabilization. We have investigated if Casp2 could mediate perinatal ischemic brain damage. METHODS: Casp2 expression in human neonatal brains and developmental patterns in rats and mice were evaluated. Casp2-deficient (Casp2(-/-) ), wild-type (WT), and heterozygous (Casp2(+/-) ) newborn C57BL/6 mice were subjected to hypoxia-ischemia (unilateral carotid occlusion + exposure to 10% oxygen for 50 minutes) or intracerebral injection of the excitotoxic N-methyl-D-aspartate-receptor agonist ibotenate. In addition, Casp2 specific siRNAs were preinjected into the brain of WT newborn mice 24 hours before ibotenate treatment. Brain tissues were examined by immunohistochemical staining (cresyl violet, MAP2, NF68, Casp2, Casp3) and Western blotting. Lesion volumes and injury in the cortical plates and white matter were quantified together with activated Casp3. RESULTS: Casp2 is highly expressed in the neonatal brain. Casp2-deficient mice subjected to hypoxia-ischemia at postnatal day 9 present significantly lower cerebral infarction, reduced white matter injury, and reduced Casp3 activation in the thalamus and hippocampus. Both Casp2(-/-) mice and siRNA-administered WT mice conferred reduction of gray and white matter injury after excitotoxic insult at postnatal day 5. Casp3 activation was also found reduced in Casp2-deficient mice subjected to excitotoxicity. INTERPRETATION: These data suggest for the first time a role of Casp2 in neonatal brain damage. ANN NEUROL 2011;
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| 3. |
- Dean, Justin M, et al.
(författare)
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Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep.
- 2011
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:5, s. 846-856
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Preterm infants exhibit chronic deficits in white matter (WM) and cortical maturation. Although fetal infection/inflammation may contribute to WM pathology, the factors contributing to cortical changes are largely unknown. We examined the effect of fetal lipopolysaccharide (LPS) exposure on WM and cortical development as assessed by magnetic resonance imaging (MRI), electroencephalography (EEG), and histopathology in fetal sheep at preterm human equivalent age. METHODS: LPS was administered to fetal sheep at 102.5 ± 0.5 days of gestation. Continuous biophysical recordings were analyzed for 10 days after LPS. At postmortem, measurement of cerebral WM and cortical tissue volumes was achieved by stereological techniques. Specific effects of LPS on MRI-assessed T(1) -weighted and T(2) -weighted images, and immunohistochemical expression of oligodendrocytes, proliferating cells, cortical NeuN-positive and Nurr1-positive neurons (subplate marker), and cell death mechanisms were examined. RESULTS: We observed reductions in WM (∼21%; LPS, 1.19 ± 0.04 vs control, 1.51 ± 0.07cm(3) ; p < 0.001) and cortical (∼18%; LPS, 2.34 ± 0.10 vs control, 2.85 ± 0.07cm(3) ; p < 0.001) volumes, associated with overt and diffuse WM injury, T(1) -/T(2) -weighted signal alterations, and reduced numbers of WM oligodendrocytes (LPS, 485 ± 31 vs control, 699 ± 69 cells/mm(2) ; p = 0.0189) and NeuN-positive (LPS, 421 ± 71 vs control 718 ± 92 cells/mm(2) ; p = 0.04) and Nurr1-positive (control, 2.5 ± 0.6 vs LPS, 0.6 ± 0.1 cells/mm(2) ; p = 0.007) cortical neurons after LPS. Moreover, there was loss of the normal maturational increase in cortical EEG amplitude, which correlated with reduced cortical volumes. INTERPRETATION: Fetal exposure to LPS prior to myelination onset can impair both white matter and cortical development in a preclinical large animal model, supporting a role for maternal/fetal infection in the pathogenesis of preterm brain injury. ANN NEUROL 2011.
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| 4. |
- 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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| 5. |
- Hagberg, Henrik, 1955, et al.
(författare)
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Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults.
- 2012
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 71:4, s. 444-57
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is increasingly recognized as being of both physiological and pathological importance in the immature brain. The rationale of this review is to present an update on this topic with focus on long-term consequences of inflammation during childhood and in adults. The immature brain can be exposed to inflammation in connection with viral or bacterial infection during pregnancy or as a result of sterile central nervous system (CNS) insults. Through efficient anti-inflammatory and reparative processes, inflammation may resolve without any harmful effects on the brain. Alternatively, inflammation contributes to injury or enhances CNS vulnerability. Acute inflammation can also be shifted to a chronic inflammatory state and/or adversely affect brain development. Hypothetically, microglia are the main immunocompetent cells in the immature CNS, and depending on the stimulus, molecular context, and timing, these cells will acquire various phenotypes, which will be critical regarding the CNS consequences of inflammation. Inflammation has long-term consequences and could speculatively modify the risk of a variety of neurological disorders, including cerebral palsy, autism spectrum disorders, schizophrenia, multiple sclerosis, cognitive impairment, and Parkinson disease. So far, the picture is incomplete, and data mostly experimental. Further studies are required to strengthen the associations in humans and to determine whether novel therapeutic interventions during the perinatal period can influence the occurrence of neurological disease later in life.
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| 6. |
- Nijboer, Cora H, et al.
(författare)
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Targeting the p53 pathway to protect the neonatal ischemic brain.
- 2011
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate whether inhibition of mitochondrial p53 association using pifithrin-μ (PFT-μ) represents a potential novel neuroprotective strategy to combat perinatal hypoxic-ischemic (HI) brain damage. METHODS: Seven-day-old rats were subjected to unilateral carotid artery occlusion and hypoxia followed by intraperitoneal treatment with PFT-μ, an inhibitor of p53 mitochondrial association or PFT-α an inhibitor of p53 transcriptional activity. Cerebral damage, sensorimotor and cognitive function, apoptotic pathways (cytosolic cytochrome c, Smac/DIABLO, active caspase 3), and oxidative stress (lipid peroxidation and PARP-1 cleavage) were investigated. RESULTS: PFT-μ treatment completely prevented the HI-induced increase in mitochondrial p53 association at 3 hours and reduced neuronal damage at 48 hours post-HI. PFT-μ had long-term (6-10 weeks post-HI) beneficial effects as sensorimotor and cognitive outcome improved and infarct size was reduced by ∼79%. Neuroprotection by PFT-μ treatment was associated with strong inhibition of apoptotic pathways and reduced oxidative stress. Unexpectedly, PFT-μ also inhibited HI-induced upregulation of p53 target genes. However, the neuroprotective effect of inhibiting only p53 transcriptional activity by PFT-α was significantly smaller and did not involve reduced oxidative stress. INTERPRETATION: We are the first to show that prevention of mitochondrial p53 association by PFT-μ strongly improves functional outcome and decreases lesion size after neonatal HI. PFT-μ not only inhibits mitochondrial release of cytochrome c, but also inhibits oxidative stress. We propose that as a consequence nuclear accumulation of p53 and transcription of proapoptotic target genes are prevented. In conclusion, targeting p53 mitochondrial association by PFT-μ may develop into a novel and powerful neuroprotective strategy. ANN NEUROL 2011;00:000-000.
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| 7. |
- Wang, Xiaoyang, 1965, et al.
(författare)
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N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury.
- 2007
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Ingår i: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 61:3, s. 263-71
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC), in a clinically relevant model. METHODS: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI. RESULTS: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation. INTERPRETATION: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury.
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