| 1. |
- Miller, S. L., et al.
(författare)
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The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome
- 2016
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751. ; 594:4, s. 807-823
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Tidskriftsartikel (refereegranskat)abstract
- Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions.
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| 2. |
- Hammarlund, Maria, et al.
(författare)
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The selectivealpha7 nicotinic acetylcholine receptor agonist AR‑R17779 does not affect ischemia-reperfusion brain injury in mice.
- 2021
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Ingår i: Bioscience reports. - 1573-4935. ; 41:6
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation plays a central role in stroke-induced brain injury. The alpha7 nicotinic acetylcholine receptor (α7nAChR) can modulate immune responses in both the periphery and the brain. The aims of this study were to investigate α7nAChR expression in different brain regions and evaluate the potential effect of the selective α7nAChR agonist AR-R17779 on ischemia-reperfusion brain injury in mice. Droplet digital PCR (ddPCR) was used to evaluate the absolute expression of the gene encoding α7nAChR (Chrna7) in hippocampus, striatum, thalamus and cortex in adult, naïve mice. Mice subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery were treated with α7nAChR agonist AR-R17779 (12 mg/kg) or saline once daily for five days. Infarct size and microglial activation seven days after tMCAO were analyzed using immunohistochemistry. Chrna7 expression was found in all analyzed brain regions in naïve mice, with the highest expression in cortex and hippocampus. At sacrifice, white blood cell count was significantly decreased in AR-R17779 treated mice compared with saline controls in the sham groups, although, no effect was seen in the tMCAO groups. Brain injury and microglial activation was evident seven days after tMCAO. However, no difference was found between mice treated with saline or AR‑R17779. In conclusion, α7nAChR expression varies in different brain regions and, despite a decrease in white blood cells in sham mice receiving AR-R17779, this compound does not affect stroke-induced brain injury.
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| 3. |
- Thordstein, Magnus, et al.
(författare)
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Effects of inflammation on cerebral electric activity in fetal sheep
- 2008
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Ingår i: 2nd Congress of the European Academy of Paediatrics, Nice 23-28 okt 2008.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVE Intrauterine infections can by themselves induce fetal brain damage but also potentiate the effects of other harmful influences such as asphyxia and seizures. Using an EEG technique that permits the recording of extremely low frequencies, often called DC EEG, changes in the level, i.e. DC shifts can be detected. The DC level has been suggested to depend mainly on the potential over the blood brain barrier (BBB), in turn decided primarily by the arterial level of pCO2. Fetuses affected by infection/inflammation that produce detrimental effects on the brain, may have elevated levels of pCO2 and disturbance of the BBB. We aimed at investigating the possibility that the DC EEG could be used to detect the effects of inflammation on the fetal brain. METHODS Fetal sheep were instrumented at 97 days of gestation with catheters, four active EEG electrodes placed on the dura mater as well as extracranial reference and ground electrodes. After three days of recovery, the bacterial endotoxin lipopolysaccharide (LPS) was given to the fetus (200 ng i.v.). RESULTS Exposure to LPS induced a positive DC shift in parallel to the assumed affection of cerebral function and to the pCO2 elevation. This change was not always obvious in standard EEG. CONCLUSIONS These recordings of fetal DC EEG appear to be the first to be done. They indicate that the effects of inflammation on cerebral function can be monitored by DC EEG. Such monitoring might be feasible also during late stages of labour and in neonates.
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| 4. |
- Persson, Åsa, 1980, et al.
(författare)
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Radixin expression in microglia after cortical stroke lesion
- 2013
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Ingår i: Glia. - : Wiley. - 0894-1491. ; 61:5, s. 790-799
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Tidskriftsartikel (refereegranskat)abstract
- Stroke induces extensive tissue remodeling, resulting in the activation of several cell types in the brain as well as recruitment of blood-borne leucocytes. Radixin is part of a cytoskeleton linker protein family with the ability to connect transmembrane proteins to the actin cytoskeleton, promoting cell functions involving a dynamic cytoskeleton such as morphological changes, cell division and migration which are common events of different cell types after stroke. In the healthy adult brain radixin is expressed in Olig2+ cells throughout the brain and in neural progenitor cells in the subventricular zone. In the current study, we detected a 2.5 fold increase in the number of radixin positive cells in the peri-infarct cortex two weeks after the induction of cortical stroke by photothrombosis. Similarly, the number of Olig2+ cells increased in the peri-infarct area after stroke; however, the number of radixin+/Olig2+ cells was unchanged. Neural progenitor cells maintained radixin expression on their route to the infarct. More surprising however, was the expression of radixin in activated microglia in the peri-infarct cortex. Seventy percent of Iba1+ cells expressed radixin after stroke, a population which was not present in the control brain. Furthermore, activation of radixin was predominantly detected in the peri-infarct region of oligodendrocyte progenitors and microglia. The specific location of radixin+ cells in the peri-infarct region and in microglia suggests a role for radixin in microglial activation after stroke.
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| 5. |
- Hellgren, Gunnel, 1961, et al.
(författare)
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Safety aspects of longitudinal administration of IGF-I/IGFBP-3 complex in neonatal mice.
- 2011
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Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1532-2238. ; 21:4, s. 205-11
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Very preterm birth is associated with a high risk of morbidity. Infants born very preterm have low serum levels of insulin-like growth factor I (IGF-I), that further decrease after birth. IGF-I is essential for brain development and low serum levels have been associated with retinopathy of prematurity. The present study aimed to investigate the effects of prolonged administration of a low dose of rhIGF-I/rhIGFBP-3 on glucose levels and total body weight, as well as liver, spleen and brain weights, and gray and subcortical white matter in newborn mice. DESIGN: The study was performed as three different trials. In all experiments C57BL/6N mice were injected with a rhIGF-I/rhIGFBP-3 complex or saline. In the first experimental trial, blood glucose levels were assessed 30min, 1h, 1.5h, 3h, 6h, 24h and 48h after the rhIGF-I/rhIGFBP-3 or saline injection on postnatal day (PND) 6. In the second trial, mice were injected daily from PND 3 to 11 and sacrificed on PND 12 for analysis of IGF-I serum levels. In the third trial, body and organ weights and effects on gray and white matter were assessed on PND 18 after PND 3-11 treatments as above. Effects on gray and white matter were measured using immunoreactivity for microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), neurofilament and oligodendrocyte lineage transcription factor 2 (Olig2). RESULTS: Blood glucose levels were unchanged in the rhIGF-I/rhIGFBP-3-treated group compared to baseline. In the control group glucose levels increased 30min after the second saline injection; levels were not elevated at the subsequent time point. Three hours after the rhIGF-I/rhIGFBP-3 or saline, glucose levels were lower in rhIGF-I/rhIGFBP-3-treated animals than in saline treated (p=0.026). At PND 18, total body weight was higher in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.05), but there were no differences between groups in brain, liver or spleen weights. No differences in gray matter area were found between groups. Analyses of white matter markers showed an increased number of Olig2-positive cells in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.001). There were no differences between groups in terms of MBP, CNPase or neurofilament immunoreactivity. CONCLUSIONS: Prolonged administration of rhIGF-I/rhIGFBP-3 did not have a negative impact on blood glucose levels and was beneficial for total body growth.
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| 6. |
- Thordstein, Magnus, et al.
(författare)
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Effects of inflammation on cerebral electric activity in fetal sheep
- 2007
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Ingår i: Sjätte Graz-symposiet om utvecklings-neurologi, Graz 3-5 maj 2007.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVEIntrauterine infections can by themselves induce fetal brain damage but also potentiate the effects of other harmful influences such as asphyxia and seizures. Using an EEG technique that permits the recording of extremely low frequencies, often called DC EEG, changes in the level, i.e. DC shifts can be detected. The DC level has been suggested to depend mainly on the potential over the blood brain barrier (BBB), in turn decided primarily by the arterial level of pCO2.Fetuses affected by infection/inflammation that produce detrimental effects on the brain, may have elevated levels of pCO2 and disturbance of the BBB. We aimed at investigating the possibility that the DC EEG could be used to detect the effects of inflammation on the fetal brain.METHODSFetal sheep were instrumented at 97 days of gestation with catheters, four active EEG electrodes placed on the dura mater as well as extracranial reference and ground electrodes. After three days of recovery, the bacterial endotoxin lipopolysaccharide (LPS) was given to the fetus (200 ng i.v.).RESULTSExposure to LPS induced a positive DC shift in parallel to the assumed affection of cerebral function and to the pCO2 elevation. This change was not always obvious in standard EEG.CONCLUSIONSThese recordings of fetal DC EEG appear to be the first to be done. They indicate that the effects of inflammation on cerebral function can be monitored by DC EEG. Such monitoring might be feasible also during late stages of labour and in neonates.
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| 7. |
- Chavez-Valdez, R., et al.
(författare)
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Evidence for Sexual Dimorphism in the Response to TLR3 Activation in the Developing Neonatal Mouse Brain: A Pilot Study
- 2019
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptor (TLR)3 activation during the neonatal period produces responses linked to the origins of neuropsychiatric disorders. Although there is sexual dimorphism in neuropsychiatric disorders, it is unknown if brain responses to TLR3 activation are sex-specific. We hypothesized that poly I:C in a post-natal day (P)8 model induces a sexually dimorphic inflammatory responses. C57BL6 mice received intraperitoneal injection of poly I:C (10 mg/kg) or vehicle [normal saline (NS)] at P8. Pups were killed at 6 or 14 h for caspase 3 and 8 activity assays, NFkB ELISA, IRF3, AP1, and GFAP western blotting and cytokines/chemokines gene expression real time qRT-PCR (4-6/group). A second group of pups were killed at 24 h (P9) or 7 days (P15) after poly I:C to assess astrocytic (GFAP) and microglia (Iba1) activation in the hippocampus, thalamus and cortex using immunohistochemistry, and gene and protein expression of cytokines/chemokines using real time RT-PCR and MSD, respectively (4-6/group). Nonparametric analysis was applied. Six hours after poly I:C, caspase-3 and -8 activities in cytosolic fractions were 1.6 and 2.8-fold higher in poly I:C-treated than in NS-treated female mice, respectively, while gene expressions of pro-inflammatory cytokines were upregulated in both sexes. After poly I:C, IRF3 nuclear translocation occurred earlier (6 h) in female mice and later (14 h) in male mice. At 14 h after poly I:C, only male mice also had increased nuclear NF kappa B levels (88%, p < 0.001) and GFAP expression coinciding with persistent IL-6 and FAS gene upregulation (110 and 77%, respectively; p < 0.001) and IL-10 gene downregulation (-42%, p < 0.05). At 24 h after poly I:C, IL-1 beta, CXCL-10, TNF-alpha, and MCP-1 were similarly increased in both sexes but at 7 days after exposure, CXCL-10 and INF gamma were increased and IL-10 was decreased only in female mice. Accordingly, microglial activation persisted at 7 days after poly I:C in the hippocampus, thalamus and cortex of female mice. This preliminary study suggests that TLR3 activation may produce in the developing neonatal mouse brain a sexually dimorphic response with early activation of caspase-dependent pathways in female mice, activation of inflammatory cascades in both sexes, which then persists in female mice. Further well-powered studies are essential to confirm these sex-specific findings.
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| 8. |
- Golubinskaya, Veronika, 1974, et al.
(författare)
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Bestrophin-3 Expression in a Subpopulation of Astrocytes in the Neonatal Brain After Hypoxic-Ischemic Injury
- 2019
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Bestrophin-3, a potential candidate for a calcium-activated chloride channel, recently was suggested to have cell-protective functions. We studied the expression and alternative splicing of bestrophin-3 in neonatal mouse brain and after hypoxic-ischemic (HI) injury and in human neonatal brain samples. HI brain injury was induced in 9-day old mice by unilateral permanent common carotid artery occlusion in combination with exposure to 10% oxygen for 50 min. Endoplasmic reticulum stress was induced by thapsigargin treatment in primary culture of mouse brain astrocytes. We also investigated expression of bestrophin-3 protein in a sample of human neonatal brain tissue. Bestrophin-3 protein expression was detected with immunohistochemical methods and western blot; mRNA expression and splicing were analyzed by RT-PCR. HI induced a brain tissue infarct and a pronounced increase in the endoplasmic reticulum-associated marker CHOP. Three days after HI a population of astrocytes co-expressed bestrophin-3 and nestin in a penumbra-like area of the injured hemisphere. However, total levels of Bestrophin-3 protein in mouse cortex were reduced after injury. Mouse astrocytes in primary culture also expressed bestrophin-3 protein, the amount of which was reduced by endoplasmic reticulum stress. Bestrophin-3 protein was detected in astrocytes in the hippocampal region of the human neonatal brain which had patchy white matter gliosis and neuronal loss in the Sommer's sector of the Ammon's horn (CA1). Analysis of bestrophin-3 mRNA in mouse brain with and without injury showed the presence of two truncated spliced variants, but no full-length mRNA. Total amount of bestrophin-3 mRNA increased after HI, but showed only minor injury-related change. However, the splice variants of bestrophin-3 mRNA were differentially regulated after HI depending on the presence of tissue injury. Our results show that bestrophin-3 is expressed in neonatal mouse brain after injury and in the human neonatal brain with pathology. In mouse brain bestrophin-3 protein is upregulated in a specific astrocyte population after injury and is co-expressed with nestin. Splice variants of bestrophin-3 mRNA respond differently to HI, which might indicate their different roles in tissue injury.
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| 9. |
- Hall, Ulrika Andersson, et al.
(författare)
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Central and Peripheral Leptin and Agouti-Related Protein during and after Pregnancy in Relation to Weight Change.
- 2018
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Ingår i: Clinical endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 88:2, s. 263-271
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Tidskriftsartikel (refereegranskat)abstract
- To study changes of neuropeptides and adipokines in cerebrospinal fluid (CSF) and serum from pregnancy to post-pregnancy in relation to weight changes, fat mass and glucose metabolism.With high postpartum weight retention being a risk factor in future pregnancies and of life-long obesity we evaluated neuropeptide and adipokine changes in women who either gained weight or were weight stable.Women were followed for 5±1 years after pregnancy and divided into two groups, Weight-Stable and Weight-Gain, by weight change from start of pregnancy.Twenty-five women (BMI 27±5kg/m2 ) recruited at admission for elective caesarean section.CSF and serum levels of agouti-related protein (AgRP), leptin, and insulin, and serum levels of adiponectin and soluble leptin receptor were measured during and after pregnancy. These measurements were further related to fat mass and insulin sensitivity (HOMA-IR).S-AgRP levels during pregnancy were lower in the Weight-Stable group and a 1 unit increase in s-AgRP was associated with 24% higher odds of pertaining to the Weight-Gain group. After pregnancy, s-AgRP increased in the Weight-Stable group but decreased in the Weight-Gain group. Decreased transport of leptin into CSF during pregnancy was reversed by an increased CSF:serum leptin ratio after pregnancy. In women who returned to their pre-pregnancy weight, serum adiponectin increased after pregnancy and correlated negatively with HOMA-IR.S-AgRP concentration in late pregnancy may be one factor predicting weight change after pregnancy, and circulating AgRP may be physiologically important in the long-term regulation of body weight. This article is protected by copyright. All rights reserved.
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| 10. |
- Stridh, Linnea, 1983, et al.
(författare)
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Toll-like receptor-3 activation increases the vulnerability of the neonatal brain to hypoxia-ischemia.
- 2013
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 33:29, s. 12041-51
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Tidskriftsartikel (refereegranskat)abstract
- Susceptibility and progression of brain injury in the newborn is closely associated with an exacerbated innate immune response, but the underlying mechanisms are often unclear. Toll-like receptors (TLRs) are important innate immune sensors that may influence the vulnerability of the developing brain. In the current study, we provide novel data to show that activation of the viral innate immune receptor TLR-3 sensitizes the neonatal brain to subsequent hypoxic-ischemic (HI) damage. Poly inosinic:poly cytidylic acid (Poly I:C), a synthetic ligand for TLR-3, was administered to neonatal mice 14 h before cerebral HI. Activation of TLR-3 before HI increased infarct volume from 3.0 ± 0.5 to 15.4 ± 2.1 mm³ and augmented loss of myelin basic protein from 13.4 ± 6.0 to 70.6 ± 5.3%. The sensitizing effect of Poly I:C was specific for the TLR-3 pathway because mice deficient in the TLR-3 adaptor protein Toll/IL-1R domain-containing adaptor molecule-1 (TRIF) did not develop larger brain damage. The increased vulnerability was associated with a TRIF-dependent heightened inflammatory response, including proinflammatory cytokines, chemokines, and the apoptosis-associated mediator Fas, whereas there was a decrease in reparative M2-like CD11b⁺ microglia and phosphorylation of Akt. Because TLR-3 is activated via double-stranded RNA during most viral infections, the present study provides evidence that viral infections during pregnancy or in the neonate could have great impact on subsequent HI brain injury.
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