| 1. |
- Blomstrand, Malin, 1974, et al.
(författare)
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No clinically relevant effect on cognitive outcomes after low-dose radiation to the infant brain: A population-based cohort study in Sweden
- 2014
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 53:9, s. 1143-1150
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Tidskriftsartikel (refereegranskat)abstract
- While the detrimental effects of cranial radiotherapy on the developing brain are well known, the effects on cognitive performance of low doses of ionizing radiation is less studied. We performed a population-based cohort study to determine whether low doses of ionizing radiation to the brain in infancy affects cognitive function later in life. Further we hypothesized that the dose to the hippocampus predicts cognitive late side effects better than the anterior or the posterior brain doses. Material and methods. During 1950 - 1960 3860 boys were treated with radiation in Sweden for cutaneous hemangiomas before the age of 18 months. Of these, 3030 were analyzed for military test scores at the age of 18 years and 2559 for the highest obtained educational level. Results. Logical, spatial and technical test scores were not affected by increasing irradiation doses. The verbal test scores displayed a significant trend for decreasing scores with increasing doses to the hippocampus (p = 0.005). However, the absolute mean difference between the zero dose and the highest dose category (median 680 mGy) was very small, only 0.64 stanine points, and the significance was dependent on the highest dose category, containing few subjects. The educational level was not affected by brain irradiation. Overall, the hippocampal dose was a better predictor of late cognitive side effects than the doses to the anterior or the posterior brain. In conclusion, there was no decrease in logical, spatial and technical verbal or global test scores after ionizing radiation doses up to 250 mGy, but a subtle decrease in verbal test scores if the highest dose category was included (median 680 mGy). However, the clinical relevance of this decline in the highest dose group is questionable, since we could not find any effect on the highest obtained educational level.
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| 2. |
- 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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| 3. |
- Karlsson, Niklas, et al.
(författare)
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Learning and activity after irradiation of the young mouse brain analyzed in adulthood using unbiased monitoring in a home cage environment.
- 2011
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Ingår i: Radiation research. - 1938-5404. ; 175:3, s. 336-46
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy during the treatment of pediatric malignancies may cause adverse late effects. It is important to find methods to assess the functional effects of ionizing radiation in animal models and to evaluate the possible ameliorating effects of preventive or reparative treatment strategies. We investigated the long-term effects of a single 8-Gy radiation dose to the brains of 14-day-old mice. Activity and learning were evaluated in adulthood using open field and trace fear conditioning (TFC). These established methods were compared with the novel IntelliCage platform, which enables unbiased analysis of both activity and learning over time in a home cage environment. Neither activity nor learning was changed after irradiation, as judged by the open field and TFC analyses. The IntelliCage, however, revealed both altered activity and learning impairment after irradiation. Place learning and reversal learning were both impaired in the IntelliCage 3 months after irradiation. These results indicate that activity and learning should be assessed using multiple methods and that unbiased analysis over time in a home cage environment may offer advantages in the detection of subtle radiation-induced effects on the young brain.
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| 4. |
- Badiola, N, et al.
(författare)
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Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12.
- 2011
-
Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia-ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2α-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress.
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| 5. |
- Barlind, Anna, 1978, et al.
(författare)
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Decreased cytogenesis in the granule cell layer of the hippocampus and impaired place learning after irradiation of the young mouse brain evaluated using the IntelliCage platform.
- 2010
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Ingår i: Experimental brain research. - : Springer Science and Business Media LLC. - 1432-1106 .- 0014-4819. ; 201:4, s. 781-787
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Tidskriftsartikel (refereegranskat)abstract
- Radiation therapy is used to treat malignant tumors in the brain and central nervous system involvement of leukemia and lymphomas in children. However, ionizing radiation causes a number of adverse long-term side effects in the brain, including cognitive impairment. Hippocampal neurogenesis is important for place learning and has been shown to be decreased by irradiation (IR) in rats and mice. In the present study, 10-day-old male mice received 6-Gy IR to the brain on postnatal day 10. We used BrdU labeling of the granule cell layer (GCL) of the hippocampus to evaluate cell proliferation and survival. An unbiased, automated platform for monitoring of behavior in a group housing environment (IntelliCage) was used to evaluate place learning 2 months after IR. We show that cranial IR impaired place learning and reduced BrdU labeling by 50% in the GCL. Cranial IR also reduced whole body weight gain 5%. We conclude that this experimental paradigm provides a novel and time-saving model to detect differences in place learning in mice subjected to IR. This method of detecting behavioral differences can be used for further studies of adverse effects of IR on hippocampal neurogenesis and possible new strategies to ameliorate the negative effects of IR on cognition.
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| 6. |
- Barlind, Anna, 1978, et al.
(författare)
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The growth hormone secretagogue hexarelin increases cell proliferation in neurogenic regions of the mouse hippocampus.
- 2010
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Ingår i: Growth hormone & IGF research. - : Elsevier BV. - 1532-2238 .- 1096-6374. ; 20:1, s. 49-54
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Radiation therapy (RT) to the brain is often used in the treatment of children with different types of malignant diseases affecting the brain. However, RT in childhood may also have severe side effects including impaired brain maturation and intellectual development. For childhood cancer survivors these adverse effects of RT can cause lifelong disability and suffering. Therefore, there is an unmet need to limit late effects after RT. Precursor cells in the subgranular zone of the dentate gyrus (DG) in the hippocampus are particularly sensitive to irradiation (IR). This may be of significance as newly generated neurons in the DG are important for memory and learning. GH secretagogues (GHS) have previously been shown to promote neurogenesis and to have neuroprotective effects. In addition, several parts of the brain, including the hippocampus, have been shown to express the GHS receptor 1a (GHS-R1a). The aim of this study was to evaluate the potential effect of the GHS hexarelin on proliferation and survival of progenitor cells in the hippocampus after brain IR in a mouse model. DESIGN: In the present study, 10-day-old male mice received 6Gy cranial IR. Non-irradiated sham animals were used as controls. We treated one group of irradiated and one sham group with hexarelin (100mug/kg/day) for 28days and used immunohistochemical labeling of bromo-deoxy uridine (BrdU) and phospho-histone H3 of the granular cell layer of the DG to evaluate proliferation and cell survival after IR at postnatal day ten. RESULTS: Our results show that hexarelin significantly increased the number of BrdU-positive cells in the granule cell layer by approximately 50% compared to controls. CONCLUSION: The increased number of BrdU-positive cells in the granule cell layer suggests a partial restoration in the pool of proliferating cells by hexarelin after IR.
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| 7. |
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| 8. |
- Bi, D., et al.
(författare)
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The association between sex-related interleukin-6 gene polymorphisms and the risk for cerebral palsy
- 2014
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between genetic factors and the development of cerebral palsy (CP) has recently attracted much attention. Polymorphisms in the genes encoding proinflammatory cytokines have been shown to be associated with susceptibility to perinatal brain injury and development of CP. Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a pivotal role in neonatal brain injury, but conflicting results have been reported regarding the association between IL-6 single nucleotide polymorphisms (SNPs) and CP. The purpose of this study was to analyze IL-6 gene polymorphisms and protein expression and to explore the role of IL-6 in the Chinese CP population. Methods: A total of 753 healthy controls and 713 CP patients were studied to detect the presence of five SNPs (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL-6 locus. Of these, 77 healthy controls and 87 CP patients were selected for measurement of plasma IL-6 by Luminex assay. The SHEsis program was used to analyze the genotyping data. For all comparisons; multiple testing on each individual SNP was corrected by the SNPSpD program. Results: There were no differences in allele or genotype frequencies between the overall CP patients and controls among the five genetic polymorphisms. However, subgroup analysis found significant sex-related differences in allele and genotype frequencies. Differences were found between spastic CP and controls in males for rs2069837; between CP with periventricular leukomalacia and controls in males for rs1800796 and rs2066992; and between term CP and controls in males for rs2069837. Plasma IL-6 levels were higher in CP patients than in the controls, and this difference was more robust in full-term male spastic CP patients. Furthermore, the genotype has an effect on IL-6 synthesis. Conclusions: The influence of IL-6 gene polymorphisms on IL-6 synthesis and the susceptibility to CP is related to sex and gestational age.
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| 9. |
- Blomgren, Klas, 1963, et al.
(författare)
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Injury and repair in the immature brain.
- 2013
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Ingår i: Translational stroke research. - : Springer Science and Business Media LLC. - 1868-601X .- 1868-4483. ; 4:2, s. 135-136
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Blomstrand, Malin, 1974, et al.
(författare)
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Different reactions to irradiation in the juvenile and adult hippocampus
- 2014
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Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 90:9, s. 807-815
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cranial radiotherapy is an important tool in the cure of primary brain tumors. Unfortunately, it is associated with late-appearing toxicity to the normal brain tissue, including cognitive impairment, particularly in children. The underlying mechanisms are not fully understood but involve changes in hippocampal neurogenesis. Recent studies report essentially different responses in the juvenile and the adult brain after irradiation, but this has never been verified in a comparative study. Materials and methods: We subjected juvenile (9-day-old) and adult (6-month-old) male rats to a single dose of 6 Gray (Gy) whole brain irradiation and euthanized them 6 hours, 7 days or 4 weeks later. Hippocampal lysates were analyzed for caspase-3 activity (apoptosis) and the expression of cytokines, chemokines and growth factors. Four weeks after irradiation, the number of microglia (expressing ionized calcium-binding adapter molecule 1, Iba-1), activated microglia (expressing cluster of differentiation 68 [CD68]), bromodeoxyuridine (BrdU) incorporation and granule cell layer (GCL) volume were assessed. Results: The major findings were (i) higher baseline BrdU incorporation (cell proliferation) in juvenile than in adult controls, which explains the increased susceptibility to irradiation and higher level of acute cell death (caspase activity) in juvenile rats, leading to impaired growth and subsequently a smaller dentate gyrus volume 4 weeks after irradiation, (ii) more activated (CD68-positive) microglia in adult compared to juvenile rats, regardless of irradiation, and (iii) differently expressed cytokines and chemokines after cranial irradiation in the juvenile compared to the adult rat hippocampus, indicating a more pro-inflammatory response in adult brains. Conclusion: We found essentially diverse irradiation reactions in the juvenile compared to the adult hippocampus, indicating different mechanisms involved in degeneration and regeneration after injury. Strategies to ameliorate the cognitive deficits after cranial radiotherapy should therefore likely be adapted to the developmental level of the brain.
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| 11. |
- Blomstrand, Malin, et al.
(författare)
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Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma.
- 2012
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 14:7, s. 882-889
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Tidskriftsartikel (refereegranskat)abstract
- We sought to assess the feasibility and estimate the benefit of sparing the neurogenic niches when irradiating the brain of pediatric patients with medulloblastoma (MB) based on clinical outcome data. Pediatric MB survivors experience a high risk of neurocognitive adverse effects, often attributed to the whole-brain irradiation that is part of standard management. Neurogenesis is very sensitive to radiation, and limiting the radiation dose to the hippocampus and the subventricular zone (SVZ) may preserve neurocognitive function. Radiotherapy plans were created using 4 techniques: standard opposing fields, intensity-modulated radiotherapy (IMRT), intensity-modulated arc therapy (IMAT), and intensity-modulated proton therapy (IMPT). Mean dose to the hippocampus and SVZ (mean for both sites) could be limited to 88.3% (range, 83.6%-91.0%), 77.1% (range, 71.5%-81.3%), and 42.3% (range, 26.6%-51.2%) with IMAT, IMRT, and IMPT, respectively, while maintaining at least 95% of the prescribed dose in 95% of the whole-brain target volume. Estimated risks for developing memory impairment after a prescribed dose of 23.4 Gy were 47% (95% confidence interval [CI], 21%-69%), 44% (95% CI, 21%-65%), 41% (95% CI, 22%-60%), and 33% (95% CI, 23%-44%) with opposing fields, IMAT, IMRT, and IMPT, respectively. Neurogenic niche sparing during cranial irradiation of pediatric patients with MB is feasible and is estimated to lower the risks of long-term neurocognitive sequelae. Greatest sparing is achieved with intensity-modulated proton therapy, thus making this an attractive option to be tested in a prospective clinical trial.
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| 12. |
- Boström, Martina, et al.
(författare)
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Irradiation to the young mouse brain caused long-term, progressive depletion of neurogenesis but did not disrupt the neurovascular niche
- 2013
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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. - : SAGE Publications. - 1559-7016. ; 33:6, s. 935-943
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the effects of ionizing radiation on microvessel structure and complexity in the hippocampus. We also assessed neurogenesis and the neurovascular niche. Postnatal day 14 male C57BL/6 mice received a single dose of 8Gy to the whole brain and were killed 6 hours, 1 week, 7 weeks, or 1 year later. Irradiation decreased the total number of microvessels and branching points from 1 week onwards and decreased the total microvessel area 1 and 7 weeks after irradiation. After an initial increase in vascular parameter densities, concomitant with reduced growth of the hippocampus, the densities normalized with time, presumably adapting to the needs of the surrounding nonvascular tissue. Irradiation decreased the number of neural stem and progenitor cells in the hippocampus. The relative loss increased with time, resulting in almost completely ablated neurogenesis (DCX(+) cells) 1 year after irradiation (77% decreased 1 week, 86% decreased 7 weeks, and 98% decreased 1 year after irradiation compared with controls). After irradiation, the distance between undifferentiated stem cells and microvessels was unaffected, and very few dying endothelial cells were detected. Taken together, these results indicate that the vasculature adjusts to the surrounding neural and glial tissue after irradiation, not vice-versa.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 March 2013; doi:10.1038/jcbfm.2013.34.
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| 13. |
- Boström, Martina, et al.
(författare)
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The hippocampal neurovascular niche during normal development and after irradiation to the juvenile mouse brain.
- 2014
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Ingår i: International journal of radiation biology. - : Informa UK Limited. - 1362-3095 .- 0955-3002. ; 90:9, s. 778-89
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the effects of cranial irradiation on the neurovascular niche in the young brain. Disruption of this niche has previously been observed in the adult rat brain after irradiation.We subjected postnatal day 14 (P14) mice to a single dose of 8 Gy whole brain irradiation and measured the distance between microvessels and either neural progenitor cells (doublecortin-positive, DCX(+)) or proliferating cells (Ki-67(+)) in the dorsal hippocampal subgranular zone (SGZ) 6 hours, 1 week and 7 weeks post-irradiation. In addition, pericyte coverage of microvessels in the SGZ was measured.DCX(+) and Ki-67(+) cells were located closer to microvessels in the adult brain compared to young, still growing brains, constituting new information on normal development. We found an increased distance between microvessels and DCX(+) cells 6 h post-irradiation and between microvessels and Ki-67(+) cells 1 week post-irradiation. Furthermore, pericyte coverage was transiently decreased by 17% 6 h post-irradiation.The hippocampal neurovascular niche in the young, growing brain is transiently disrupted by irradiation. It remains to be elucidated what role these transient changes play in the apparently permanent ablation of hippocampal neurogenesis previously demonstrated in the same model.
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| 14. |
- Dobsicek Trefna, Hana, 1979, et al.
(författare)
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Antenna Applicator for Microwave Hyperthermia Treatment of Pediatric Brain Cancer
- 2014
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Ingår i: 8th European Conference on Antennas and Propagation, EuCAP 2014, The Hague, The Netherlands 6-11 April 2014. - 9788890701849
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- A novel antenna applicator for microwave hyperthermia allowing treatment of deep brain tumors is proposed. The applicator consists of up to 16 antennas placed around the head in a helmet-like set-up and operates at a frequency range of 430-1000~MHz. The self-grounded bow-tie antennas are housed in a molded plastic enclosure with the shape of a truncated cone. The inner space of the enclosure is filled with distilled water. The antennas are attached to a perimetric water bolus with a thickness of 2 cm and aligned with the head shape. The focusing ability of the applicator was investigated on a homogeneous SAM model and on a model of a 13-year old patient containing a spherical tumor of 2 cm radius. Two different tumor positions were investigated: the right frontal lobe and the central brain. The obtained SAR distributions are favorable, although a relatively high level of energy is also absorbed on the surface of the body. This heating is however not expected to cause problems as it can be cooled by blood perfusion and water bolus. Our results show that focused microwave heating in the brain is feasible and warrants further verification on phantoms.
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| 15. |
- Ghezzi, Pietro, et al.
(författare)
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Erythropoietin: not just about erythropoiesis
- 2010
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Ingår i: LANCET. - 0140-6736. ; 375:9732, s. 2142-2142
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Tidskriftsartikel (refereegranskat)abstract
- Referred to by Department of Error, The Lancet, Volume 376, Issue 9739, 7–13 August 2010, Page 418
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| 16. |
- Han, Wei, et al.
(författare)
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Delayed, Long-Term Administration of the Caspase Inhibitor Q-VD-OPh Reduced Brain Injury Induced by Neonatal Hypoxia-Ischemia.
- 2014
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Ingår i: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 36:1, s. 64-72
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis contributes greatly to the morphological and biochemical features of cell death after neonatal cerebral hypoxia-ischemia (HI), making this mode of cell death a promising therapeutic target. We previously showed that 10 mg/kg of the caspase inhibitor Q-VD-OPh at the onset of and immediately after HI on postnatal day 9 reduced brain infarct volume. In this study, delayed administration of Q-VD-OPh, 12 and 36 h after HI, decreased HI-induced caspase-3 activity (DEVD cleavage) by 23% and diminished the levels of the proinflammatory chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) by 29.3 and 29.1%, respectively, but not the levels of the anti-inflammatory cytokines IL-4 and IL-10. Long-term administration of Q-VD-OPh initiated at 12 h after HI, and continued at 24-hour intervals for 2 weeks, reduced total brain tissue loss by 31.3% from 41.5 ± 3.1 mm(3) in the vehicle group to 28.5 ± 3.0 mm(3) in the Q-VD-OPh group when evaluated 16 weeks after HI (p = 0.004). Q-VD-OPh treatment also ameliorated the loss of sensorimotor function, as evaluated by a cylinder rearing test (Q-VD-OPh: 30.8 ± 4.3% vs. vehicle: 59.7 ± 6.3% in nonimpaired forepaw preference) 3 weeks after HI, and reduced HI-induced hyperactivity, as measured in an open field test (Q-VD-OPh: 4,062 ± 198 cm vs. vehicle: 4,792 ± 205 cm in distance moved) 7 weeks after the insult. However, the functional protection was no longer observed when analyzed again at later time points. The mechanisms underlying the discrepancy between sustained morphological protection and transient functional protection remain to be elucidated. © 2014 S. Karger AG, Basel.
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| 17. |
- Hangen, E, et al.
(författare)
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A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2.
- 2010
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 17:7, s. 1155-66
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been 'designed' to be retained in mitochondria and to minimize its potential neurotoxic activity.Cell Death and Differentiation advance online publication, 29 January 2010; doi:10.1038/cdd.2009.211.
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| 18. |
- Hangen, Emilie, et al.
(författare)
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Life with or without AIF.
- 2010
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Ingår i: Trends in biochemical sciences. - : Elsevier BV. - 0968-0004. ; 35:5, s. 278-87
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Forskningsöversikt (refereegranskat)abstract
- Apoptosis-inducing factor (AIF) was initially discovered as a caspase-independent death effector. AIF fulfills its lethal function after its release from mitochondria and its translocation to the nucleus of the dying cell. The contribution of AIF to programmed cell death is dependent upon the cell type and apoptotic insult. Recent in vivo data indicate that, in addition to its lethal activity, AIF plays a vital mitochondrial role in healthy cells. A segment of AIF which is dispensable for its apoptotic function carries an NADH-oxidase domain that regulates the respiratory chain complex I and is required for cell survival, proliferation and mitochondrial integrity. Mice that express reduced levels of AIF constitute a reliable model of complex I deficiency. Here we discuss recent reports on the survival-related function(s) of AIF.
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| 19. |
- Hellström, Nina, 1976, et al.
(författare)
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Unique gene expression patterns indicate microglial contribution to neural stem cell recovery following irradiation.
- 2011
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Ingår i: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 46:4, s. 710-9
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Tidskriftsartikel (refereegranskat)abstract
- Ionizing radiation results in damage to neural stem cells and reduced neurogenesis. The aim of the present study was to determine intrinsic and extrinsic factors that influence neural stem cell survival following irradiation, using qPCR. Gene expression of hippocampal and SVZ neurospheres were analyzed following irradiation, and results demonstrated that irradiated hippocampal and SVZ stem cells displayed similar gene expression profiles for intrinsic genes. Irradiated microglia (extrinsic factor) isolated from the SVZ exhibited increased gene expression of growth factors involved in stem cell maintenance, proliferation, and survival. However, microglial genes in the irradiated hippocampus responded less favorably with respect to stem cell recovery. This might explain the superior recovery of SVZ compared to hippocampal stem cells following in vivo irradiation. In addition, our results show that a combination of growth factors, which were upregulated in SVZ microglia, increased the proliferation and decreased cell death of irradiated neurospheres in vitro.
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| 20. |
- Huo, Kaiming, et al.
(författare)
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Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain.
- 2012
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Ingår i: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 51:1-2, s. 32-42
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Tidskriftsartikel (refereegranskat)abstract
- Lithium was recently shown to inhibit apoptosis and promote survival of neural progenitor cells after hypoxia-ischemia in the immature rat brain. Our aim was to evaluate the effects of lithium on cell death and proliferation in the hippocampus after irradiation (IR) to the immature brain. Male mice were injected with 2 mmol/kg lithium chloride i.p. on postnatal day 9 (P9) and additional lithium injections, 1 mmol/kg, were administered at 24 h intervals for up to 7 days. BrdU was injected 4 h after lithium injections on P9 and P10. The left hemisphere received a single dose of 8 Gy (MV photons) on P11. The animals were euthanized 6 h or 7 weeks after IR. The number of BrdU-labeled cells in the subgranular zone (SGZ) of the granule cell layer (GCL) 6h after IR was 24% higher in the lithium-treated mice. The number of proliferating, phospho-histone H3-positive cells in the SGZ 7 weeks after IR was 59% higher in the lithium group, so the effect was long-lasting. The number of apoptotic cells in the SGZ 6 h after IR was lower in the lithium group, as judged by 3 different parameters, pyknosis, staining for active caspase-3 and TUNEL. Newly formed cells (BrdU-labeled 1 or 2 days before IR) showed the greatest degree of protection, as judged by 50% fewer TUNEL-positive cells, whereas non-BrdU-labeled cells showed 38% fewer TUNEL-positive cells 6 h after IR. Consequently, the growth retardation of the GCL was less pronounced in the lithium group. The number and size of microglia in the DG were also lower in the lithium group, indicating reduced inflammation. Learning was facilitated after lithium treatment, as judged by improved context-dependent fear conditioning, and improved place learning, as judged by assessment in the IntelliCage platform. In summary, lithium administration could decrease IR-induced neural progenitor cell apoptosis in the GCL of the hippocampus and ameliorate learning impairments. It remains to be shown if lithium can be used to prevent the debilitating cognitive late effects seen in children treated with cranial radiotherapy.
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| 21. |
- Kalm, Marie, 1981, et al.
(författare)
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Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation
- 2013
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 4:e962
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is an effective tool in the treatment of pediatric malignancies but it is associated with adverse side effects, both short- and long-term. One common long-term side effect after cranial radiotherapy is cognitive impairment and this is, at least partly, thought to be caused by reduced hippocampal neurogenesis. Neuroinflammation and a perturbed microenvironment are thought to be important in the dysregulation of neurogenesis seen after irradiation (IR). We investigated the effects of a preexisting, lipopolysaccharide (LPS)-induced systemic inflammation at the time of IR in both males and females. A single dose of 8 Gy to the brain of postnatal day 14 mice caused an upregulation of cytokinesichemokines (IL-1/1, MIP-1 IL-12, GM-CSF, MIP1 z, IL-17, CCL2 and KC) 6 h after IR, more so in females. Caspase-3 activity, reflecting apoptosis and possibly microglia activation, was elevated 6 h after IR. Females treated with LPS before IR showed a higher caspase-3 activity compared with males. During the chronic phase (3 months post IR), we found that LPS-induced inflammation at the time of IR aggravated the IR-induced injury in both male and female mice, as judged by reduced bromodeoxyuridine incorporation and neurogenesis (doublecortin-positive cells) in the hippocampus. At this late time point, the microglia density was increased by IR, more so in females, indicating long-term effects on the microenvironment. IR increased anxiety-related behavior in vehicle-, but not LPS-, treated animals. However, exploratory behavior was affected by IR in both vehicle- and LPS-treated mice. In conclusion, we found that LPS administration before IR of the young mouse brain aggravated the injury, as judged by reduced hippocampal neurogenesis. This supports the clinical practice to postpone radiotherapy if the patient shows signs of infection. Systemic inflammation is not always obvious, though, for example because of concurrent corticosteroid treatment, so careful monitoring of inflammation is warranted.
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| 22. |
- Kalm, Marie, 1981, et al.
(författare)
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Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain
- 2013
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 247, s. 402-409
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is a major cause of long-term complications in survivors of pediatric brain tumors. These complications include intellectual and memory impairments as well as perturbed growth and puberty. We investigated the long-term effects of a single 8Gy irradiation dose to the brains of 14-day-old mice. Behavior was assessed one year after irradiation using IntelliCage and open field, followed by immunohistochemical investigation of proliferation and neurogenesis in the dentate gyrus of the hippocampus. We found a 61% reduction in proliferation and survival (BrdU incorporation 4weeks prior to sacrifice), 99% decrease in neurogenesis (number of doublecortin-positive cells) and gliosis (12% higher astrocyte density) one year following irradiation. Irradiated animals displayed increased activity in a novel environment but decreased activity in their home cage. Place learning in the IntelliCage was unaffected by irradiation but reversal learning was impaired. Irradiated animals persevered in visiting previously correct corners to a higher extent compared to control animals. Hence, despite the virtual absence of neurogenesis in these old mice, spatial learning could take place. Reversal learning however, where a previous memory was replaced with a new one, was partly impaired. This model is useful to study the so called late effects of radiotherapy to the young brain and to evaluate possible interventions.
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| 23. |
- Kuhn, Hans-Georg, 1961, et al.
(författare)
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Developmental dysregulation of adult neurogenesis.
- 2011
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Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 33:6, s. 1115-22
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Forskningsöversikt (refereegranskat)abstract
- Rather than a singular event that suddenly appears during adulthood, adult neurogenesis has long been recognized as the continuation of postnatal neurogenic activity. During the first postnatal weeks, significant cellular changes occur within and adjacent to germinal matrices of the subventricular zone and dentate gyrus. The majority of granule cells are generated during this period. In addition, radial glia are transformed into astrocyte-like stem cells, the ependymal layer is formed, and the highest rates of angiogenesis, gliogenesis and myelination are observed. The first postnatal weeks are critical as the brain growth rate is maximal, and changes during this period can have a great impact on neurogenesis levels and overall brain function later in life. This review chronicles cellular changes and some of the clinically relevant dysregulations that can occur during the postnatal period, and discusses the possible impact of these changes on neurogenesis and cognitive function later in life.
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| 24. |
- Li, Hongfu, et al.
(författare)
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Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells.
- 2011
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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. - : SAGE Publications. - 1559-7016. ; 31:10, s. 2106-2115
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxic-ischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4±14.6mm(3) in controls (n=15) to 27.6±6.2mm(3) in lithium-treated animals (n=14) 7 weeks after HI (P<0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1β and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.Journal of Cerebral Blood Flow & Metabolism advance online publication, 18 May 2011; doi:10.1038/jcbfm.2011.75.
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| 25. |
- Li, Qian, 1983, et al.
(författare)
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Lithium reduces apoptosis and autophagy after neonatal hypoxia–ischemia
- 2010
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Ingår i: Cell death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 1:July 15
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is used in the treatment of bipolar mood disorder. Reportedly, lithium can be neuroprotective in models of adult brain ischemia. The purpose of this study was to evaluate the effects of lithium in a model of neonatal hypoxic–ischemic brain injury. Nine-day-old male rats were subjected to unilateral hypoxia–ischemia (HI) and 2mmol/kg lithium chloride was injected i.p. immediately after the insult. Additional lithium injections, 1mmol/kg, were administered at 24-h intervals. Pups were killed 6, 24 or 72h after HI. Lithium reduced the infarct volume from 24.7±2.9 to 13.8±3.3mm3 (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9mm3 (43.1%) compared with vehicle at 72h after HI. Injury was reduced in the cortex, hippocampus, thalamus and striatum. Lithium reduced the ischemia-induced dephosphorylation of glycogen synthase kinase-3β and extracellular signal-regulated kinase, the activation of calpain and caspase-3, the mitochondrial release of cytochrome c and apoptosis-inducing factor, as well as autophagy. We conclude that lithium could mitigate the brain injury after HI by inhibiting neuronal apoptosis. The lithium doses used were in the same range as those used in bipolar patients, suggesting that lithium might be safely used for the avoidance of neonatal brain injury.
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| 26. |
- Nodin, Christina, 1974, et al.
(författare)
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Decreased oxidative stress during glycolytic inhibition enables maintenance of ATP production and astrocytic survival.
- 2012
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Ingår i: Neurochemistry international. - : Elsevier BV. - 1872-9754 .- 0197-0186. ; 61:3, s. 291-301
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Tidskriftsartikel (refereegranskat)abstract
- Depressed energy metabolism and oxidative stress are common features in many pathological situations in the brain, including stroke. In order to investigate astrocytic responses to such stress, we induced metabolic depression in cultured rat astrocytes. Iodoacetate (IA), an inhibitor of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used and resulted in a rapid inhibition of GAPDH activity. After 1h of GAPDH inhibition the ATP levels started to decrease and were completely abolished at 4h. In parallel, the activity of reactive oxygen species (ROS) was significantly increased, followed by extensive cell death involving flipping of phosphatidylserine and translocation of apoptosis-inducing factor, but not caspase-3 activation. When IA was combined with azide, a respiratory chain complex IV inhibitor, the ATP levels decreased immediately. Interestingly, with azide present, the ROS activity remained low and the astrocytes remained viable even at very low ATP levels. Addition of exogenous ROS-scavengers prevented the IA-induced ROS activity, the ATP levels were maintained and cell death was prevented. Similar protection could be obtained when astrocytes, prior to addition of IA, were incubated with substances known to activate the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated endogenous antioxidant system. When IA was washed out, after a relatively moderate ATP depression, massive cell death occurred. This was efficiently prevented by addition of azide or ROS scavengers during the IA treatment or by pre-activation of the Nrf2 system. Our results demonstrate that astrocytes in culture can endure and recover from glycolytic inhibition if the ROS activity remained at a low level and suggest that oxidative stress can be an important component for astrocytic cell death following metabolic stress.
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| 27. |
- Osato, Kazuhiro, et al.
(författare)
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Apoptosis-inducing factor deficiency decreases the proliferation rate and protects the subventricular zone against ionizing radiation.
- 2010
-
Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 1
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy in children often leads to progressive cognitive decline. We have established a rodent model of irradiation-induced injury to the young brain. A single dose of 8Gy was administered to the left hemisphere of postnatal day 10 (P10) mice. Harlequin (Hq) mice, carrying the hypomorphic apoptosis-inducing factor AIF(Hq) mutation, express 60% less AIF at P10 and displayed significantly fewer dying cells in the subventricular zone (SVZ) 6h after IR, compared with wild type (Wt) littermates. Irradiated cyclophilin A-deficient (CypA(-/-)) mice confirmed that CypA has an essential role in AIF-induced apoptosis after IR. Hq mice displayed no reduction in SVZ size 7 days after IR, whereas 48% of the SVZ was lost in Wt mice. The proliferation rate was lower in the SVZ of Hq mice. Cultured neural precursor cells from the SVZ of Hq mice displayed a slower proliferation rate and were more resistant to IR. IR preferentially kills proliferating cells, and the slower proliferation rate in the SVZ of Hq mice may, at least partly, explain the protective effect of the Hq mutation. Together, these results indicate that targeting AIF may provide a fruitful strategy for protection of normal brain tissue against the detrimental side effects of IR.
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| 28. |
- Osman, Ahmed M, et al.
(författare)
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Transplantation of Enteric Neural Stem/Progenitor Cells into the Irradiated Young Mouse Hippocampus.
- 2014
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Ingår i: Cell transplantation. - 1555-3892. ; 23:12, s. 1657-1671
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is an effective treatment for brain tumors, but often results in cognitive deficits in survivors. Transplantation of embryonic or brain-derived neural stem/progenitor cells (BNSPCs) ameliorated cognitive impairment after irradiation (IR) in animal models. However, such an approach in patients requires a clinically relevant source of cells. We show for the first time the utilization of enteric neural stem/progenitor cells (ENSPCs) from the postnatal intestinal wall as a source of autologous cells for brain repair after injury caused byIR. Cells were isolated from the intestinal wall and propagated in vitro for one week. Differentiation assays showed that ENSPCs are multipotent and generated neurons, astrocytes and myofibroblasts.To investigate whether ENSPCs can be used in vivo, postnatal day 9 mice were subjected to a singlemoderate irradiation dose (6 or 8 Gy). Twelve days later, mice received an intrahippocampal injection of syngeneic ENSPCs. Four weeks after transplantation, 0.5% and 1% of grafted ENSPCs were detected in the dentate gyrus of sham and irradiated animals, respectively, and only 0.1%were detected after 16 weeks. Grafted ENSPCs remained undifferentiated, but failed to restore IR-induced loss of BNSPCs and the subsequent impaired growth of the dentate gyrus. We observed microglia activation, astrogliosis and loss of granule neurons associated with grafted ENSPC clusters. Transplantation of ENSPCs did not ameliorate IR-induced impaired learning and memory. In summary, while autologous ENSPC grafting to the brain worked technically, even in the absence of immunosuppression, the protocols need to be modified to improve survival and integration.
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| 29. |
- Perez-Alcazar, Marta, et al.
(författare)
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Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3.
- 2014
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Ingår i: Experimental neurology. - : Elsevier BV. - 1090-2430 .- 0014-4886. ; 253C, s. 154-164
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Tidskriftsartikel (refereegranskat)abstract
- Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance.
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| 30. |
- Piao, Chun-Shu, et al.
(författare)
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Combined inhibition of cell death induced by apoptosis inducing factor and caspases provides additive neuroprotection in experimental traumatic brain injury.
- 2012
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Ingår i: Neurobiology of disease. - : Elsevier BV. - 1095-953X .- 0969-9961. ; 46:3, s. 745-58
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal programmed cell death (PCD) contributes to delayed tissue damage after traumatic brain injury (TBI). Both caspase-dependent and caspase-independent mechanisms have been implicated, with the latter including apoptosis inducing factor (AIF). The peptidyl-proplyl isomerase Cyclophilin A (CypA) transports AIF from the cytosol to the nucleus, a key step for AIF-dependent cell death. We compared the effects of single versus combined inhibition of caspase and AIF pathways in a mouse controlled cortical impact (CCI) model, by examining the effects of CypA gene knockout (CypA(-/-)), caspase inhibition with a pan-caspase inhibitor (boc-aspartyl(OMe)-fluoromethylketone, BAF), or combined modulation. TBI caused caspase activation as well as translocation of AIF to the nucleus. Markers of caspase activation including caspase-specific fodrin cleavage fragments and number of FLIVO-positive cells were reduced in BAF-treated CypA(+/+) mice, whereas markers of AIF activation including AIF/H2AX interaction and AIF translocation to the nucleus were attenuated in CypA(-/-) mice. Each single intervention, (CypA(-/-) or BAF-treated CypA(+/+)) reduced the number of apoptotic cells (TUNEL-positive) in the cortex and improved long-term sensorimotor function; CypA(-/-) also attenuated microglial activation after injury. Importantly, BAF-treated CypA(-/-) mice, showed greater effects than either intervention alone on multiple outcomes including: reduction in TUNEL-positive cells, decrease in neuroinflammation, improved motor and cognitive recovery, and attenuation of lesion volume and neuronal loss in the hippocampus. Using two in vitro neuronal cell death models known to induce AIF-mediated PCD, we also showed that neurons from CypA(-/-) animals were protected and that effects were unrelated to caspase activation. These data indicate that AIF-mediated and caspase-dependent pathways contribute independently and in parallel to secondary injury after TBI, and suggest that combined therapeutic strategies directed at multiple PCD pathways may provide superior neuroprotection than those directed at single mechanisms.
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| 31. |
- Roughton, Karolina, 1977, et al.
(författare)
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Irradiation to the young mouse brain impaired white matter growth more in females than in males
- 2013
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Modern therapy cures 80% of all children with brains tumors, but may also cause long-lasting side effects, so called late effects. Radiotherapy is particularly prone to cause severe late effects, such as intellectual impairment. The extent and nature of the resulting cognitive deficits may be influenced by age, treatment and gender, where girls suffer more severe late effects than boys. The reason for this difference between boys and girls is unknown, but very few experimental studies have addressed this issue. Our aim was to investigate the effects of ionizing radiation on the corpus callosum (CC) in both male and female mice. We found that a single dose of 8 Gray (Gy) to the brains of postnatal day 14 mice induced apoptosis in the CC and reduced the number of proliferating cells by one third, as judged by the number of phospho-histone H3 positive cells 6 h after irradiation (IR). BrdU incorporation was reduced (62% and 42% lower in females and males, respectively) and the number of oligodendrocytes (Olig2(+) cells) was lower (43% and 21% fewer in females and males, respectively) 4 months after IR, so the lack of developing and differentiated cells was more pronounced in females. The number of microglia was unchanged in females but increased in males at this late time point. The density of microvessel profiles was unchanged by IR. This single, moderate dose of 8 Gy impaired the brain growth to some extent (8.1% and 0.4% lower brain/body weight ratio in females and males, respectively) but the CC growth was even more impaired (31% and 19% smaller in females and males, respectively) 4 months after IR compared with non-irradiated mice. In conclusion, this is the first study to our knowledge demonstrating that IR to the young rodent brain affects white matter development more in females than in males.
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| 32. |
- Roughton, Karolina, 1977, et al.
(författare)
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Lipopolysaccharide-Induced Inflammation Aggravates Irradiation-Induced Injury to the Young Mouse Brain.
- 2013
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Ingår i: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 35:5, s. 406-415
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is an effective treatment strategy in the treatment of brain tumors, but it is also a major cause of long-term complications, especially in survivors of pediatric brain tumors. Cognitive decline caused by cranial radiotherapy is thought, at least partly, to depend on injury to stem and progenitor cells in the dentate gyrus of the hippocampus. This study investigated the effects of lipopolysaccharide (LPS)-induced inflammation at the time of irradiation (IR) in the growing mouse brain. A single injection of LPS (0.3 mg/kg) was administered 24 h prior to cranial IR of 14-day-old male mice. LPS pretreatment increased the levels of the chemokine CCL2 and the cytokine IL-1β in the brain by 440 and 560%, respectively, compared to IR alone. IR disrupted hippocampal neurogenesis and the growth of the dentate gyrus, and the mice pretreated with LPS displayed an even more pronounced lack of growth than the vehicle-treated group 2 months after IR. The density of microglia was not affected, but LPS-pretreated mice displayed 48% fewer bromodeoxyuridine-positive cells and 43% fewer doublecortin-positive cells in the granule cell layer 2 months after IR compared with the vehicle-treated group. In conclusion, an ongoing inflammation in the brain at the time of IR further enhanced the IR-induced loss of neurogenesis, and may aggravate future cognitive deficits in patients treated with cranial radiotherapy.
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| 33. |
- Roughton, Karolina, 1977, et al.
(författare)
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Sex-dependent differences in behavior and hippocampal neurogenesis after irradiation to the young mouse brain.
- 2012
-
Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 36:6, s. 2763-72
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy in the treatment of pediatric malignancies may lead to cognitive deficits, and girls suffer more severe deficits than boys. However, most experimental studies are performed on male animals only. Our aim was to investigate possible long-term gender differences in response to cranial irradiation (IR). Basal neurogenesis in non-irradiated mice was higher in females but this was not apparent until the animals were adult. Male and female C57BL/6J mice received a single dose of 8Gy to the whole brain on postnatal day 14 and were killed 6h or 4months later. Proliferation in the subgranular zone of the dentate gyrus in the hippocampus, as judged by the number of phosphohistoneH3-positive cells, was reduced by half 6h after IR in both males and females. The reduced proliferation was still obvious 4months after IR. Consequently, the continuous addition of new neurons to the granule cell layer (GCL) during brain growth was reduced in irradiated mice, and the reduction was more pronounced in females. This resulted in hampered growth of the GCL, reduced bromodeoxyuridine incorporation in adulthood, and severely reduced adult neurogenesis, as judged by the number of doublecortin-positive cells in the GCL. In an open-field test, locomotor activity was increased in both males and females after IR and anxiety levels were increased, more so in females. In an IntelliCage test, place learning was impaired by IR in females but not males.
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| 34. |
- Sato, Yoshiaki, 1971, et al.
(författare)
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Grafting of neural stem and progenitor cells to the hippocampus of young, irradiated mice causes gliosis and disrupts the granule cell layer.
- 2013
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 4
-
Tidskriftsartikel (refereegranskat)abstract
- Ionizing radiation persistently reduces the pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus (DG) of the hippocampus, which may explain some of the learning deficits observed in patients treated with radiotherapy, particularly pediatric patients. A single dose of 8Gy irradiation (IR) was administered to the brains of postnatal day 14 (P14) C57BL/6 mice and 1.0 × 10(5) bromodeoxyuridine-labeled, syngeneic NSPCs were injected into the hippocampus 1 day, 1 week or 6 weeks after IR. Cell survival and phenotype were evaluated 5 weeks after grafting. When grafted 1 day post-IR, survival and neuronal differentiation of the transplanted NSPCs were lower in irradiated brains, whereas the survival and cell fate of grafted cells were not significantly different between irradiated and control brains when transplantation was performed 1 or 6 weeks after IR. A young recipient brain favored neuronal development of grafted cells, whereas the older recipient brains displayed an increasing number of cells developing into astrocytes or unidentified cells. Injection of NSPCs, but not vehicle, induced astrogliosis and reduced thickness of the dorsal blade of the GCL after 5 months. In summary, we demonstrate that age and interval between IR and grafting can affect survival and differentiation of grafted NSPCs. The observed long-term gliosis and degeneration warrant caution in the context of NSPC grafting for therapeutical purposes.
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| 35. |
- Semple, Bridgette D, et al.
(författare)
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Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species.
- 2013
-
Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 106-107, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7-10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxic-ischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development.
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| 36. |
- Sun, Yanyan, et al.
(författare)
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Apoptosis-inducing factor downregulation increased neuronal progenitor, but not stem cell, survival in the neonatal hippocampus after cerebral hypoxiaischemia.
- 2012
-
Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: A considerable proportion of all newly generated cells in the hippocampus will die before becoming fully differentiated, both under normal and pathological circumstances. The caspase-independent apoptosis-inducing factor (AIF) has not been investigated previously in this context. RESULTS: Postnatal day 8 (P8) harlequin (Hq) mutant mice, expressing lower levels of AIF, and wild type littermates were injected with BrdU once daily for two days to label newborn cells. On P10 mice were subjected to hypoxia-ischemia (HI) and their brains were analyzed 4 h, 24 h or 4 weeks later. Overall tissue loss was 63.5% lower in Hq mice 4 weeks after HI. Shortterm survival (4 h and 24 h) of labeled cells in the subgranular zone was neither affected by AIF downregulation, nor by HI. Long-term (4 weeks) survival of undifferentiated, BLBPpositive stem cells was reduced by half after HI, but this was not changed by AIF downregulation. Neurogenesis, however, as judged by BrdU/NeuN double labeling, was reduced by half after HI in wild type mice but preserved in Hq mice, indicating that primarily neural progenitors and neurons were protected. A wave of cell death started early after HI in the innermost layers of the granule cell layer (GCL) and moved outward, such that 24 h after HI dying cells could be detected in the entire GCL. CONCLUSIONS: These findings demonstrate that AIF downregulation provides not only long-term overall neuroprotection after HI, but also protects neural progenitor cells, thereby rescuing hippocampal neurogenesis.
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| 37. |
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| 38. |
- Thal, Simone E, et al.
(författare)
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Role of apoptosis inducing factor (AIF) for hippocampal neuronal cell death following global cerebral ischemia in mice.
- 2011
-
Ingår i: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 499:1, s. 1-3
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Tidskriftsartikel (refereegranskat)abstract
- The molecular mechanisms of neuronal cell death following circulatory arrest are still not fully understood. In the current study we investigated the role of apoptosis-inducing factor (AIF), a major caspase-independent mitochondrial cell death protein, for neuronal cell death following global cerebral ischemia (GCI). C57/Bl6 or low AIF expressing Harlequin mutant mice (AIF(low)) and their wild-type littermates were subjected to 10 min of GCI. DNA damage, nuclear pathology, and localization of AIF were investigated 6, 24, and 72 h after GCI by TUNEL and DAPI staining, and immunohistochemistry, respectively. Cell death of hippocampal CA1 neurons following GCI was associated with nuclear translocation of AIF, nuclear pyknosis, and DNA fragmentation, i.e. ∼80% of all TUNEL-positive neurons had nuclear AIF staining. In AIF(low) mice neuronal cell loss was reduced by 60% (p<0.02). The current experiments suggest that AIF-mediated signaling represents a novel mechanism of neuronal cell death following GCI.
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| 39. |
- Xie, Cuicui, et al.
(författare)
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Therapeutic Benefits of Delayed Lithium Administration in the Neonatal Rat after Cerebral Hypoxia-Ischemia
- 2014
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:9
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: We have previously shown that lithium treatment immediately after hypoxia-ischemia (HI) in neonatal rats affords both short-and long-term neuroprotection. The aim of this study was to evaluate possible therapeutic benefits when lithium treatment was delayed 5 days, a time point when most cell death is over. Methods: Eight-day-old male rats were subjected to unilateral HI and 2 mmol/kg lithium chloride was injected intraperitoneally 5 days after the insult. Additional lithium injections of 1 mmol/kg were administered at 24 h intervals for the next 14 days. Brain injury was evaluated 12 weeks after HI. Serum cytokine measurements and behavioral analysis were performed before sacrificing the animals. Results: Brain injury, as indicated by tissue loss, was reduced by 38.7%, from 276.5 +/- 27.4 mm(3) in the vehicle-treated group to 169.3 +/- 25.9 mm(3) in the lithium-treated group 12 weeks after HI (p<0.01). Motor hyperactivity and anxiety-like behavior after HI were normalized by lithium treatment. Lithium treatment increased neurogenesis in the dentate gyrus as indicated by doublecortin labeling. Serum cytokine levels, including IL-1 alpha, IL-1 beta, and IL-6, were still elevated as late as 5 weeks after HI, but lithium treatment normalized these cytokine levels. Conclusions: Delayed lithium treatment conferred long-term neuroprotection in neonatal rats after HI, and this opens a new avenue for future development of treatment strategies for neonatal brain injury that can be administered after the acute injury phase.
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| 40. |
- Zhang, Liqun, et al.
(författare)
-
Stimulatory effects of thyroid hormone on brain angiogenesis in vivo and in vitro.
- 2010
-
Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 30:2, s. 323-35
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Tidskriftsartikel (refereegranskat)abstract
- Thyroid hormone is critical for the proper development of the central nervous system. However, the specific role of thyroid hormone on brain angiogenesis remains poorly understood. Treatment of rats from birth to postnatal day 21 (P21) with propylthiouracil (PTU), a reversible blocker of triiodothyronine (T3) synthesis, resulted in decreased brain angiogenesis, as indicated by reduced complexity and density of microvessels. However, when PTU was withdrawn at P22, these parameters were fully recovered by P90. These changes were paralleled by an altered expression of vascular endothelial growth factor A (Vegfa) and basic fibroblast growth factor (Fgf2). Physiologic concentrations of T3 and thyroxine (T4) stimulated proliferation and tubulogenesis of rat brain-derived endothelial (RBE4) cells in vitro. Protein and mRNA levels of VEGF-A and FGF-2 increased after T3 stimulation of RBE4 cells. The thyroid hormone receptor blocker NH-3 abolished T3-induced Fgf2 and Vegfa upregulation, indicating a receptor-mediated effect. Thyroid hormone inhibited the apoptosis in RBE4 cells and altered mRNA levels of apoptosis-related genes, namely Bcl2 and Bad. The present results show that thyroid hormone has a substantial impact on vasculature development in the brain. Pathologically altered vascularization could, therefore, be a contributing factor to the neurologic deficits induced by thyroid hormone deficiency.
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| 41. |
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| 42. |
- Zhu, Changlian, 1964, et al.
(författare)
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Inhaled nitric oxide protects males but not females from neonatal mouse hypoxia-ischemia brain injury
- 2013
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 4:2, s. 201-207
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Tidskriftsartikel (refereegranskat)abstract
- It was recently discovered that while under normal conditions inhaled nitric oxide (iNO) does not affect cerebral blood flow, it selectively dilates arterioles in the ischemic penumbra during experimental cerebral ischemia, thereby increasing collateral blood flow and reducing ischemic brain damage. The mechanism was verified in multiple models, but only in male animals. Our aim was to evaluate the effects of iNO on brain injury in neonatal males and females. Nine-day-old mice were subjected to unilateral hypoxia–ischemia (HI), using 10 % oxygen balanced with nitrogen, with or without 50 ppm NO. Brain injury 72 h after HI was reduced by iNO as judged by percentage of injury (−21.7 %), atrophy (−23.7 %), and total pathological score (−29 %). The injury was significantly reduced in males (−32.4 %, p<0.05) but not in females (−7.1 %, n.s.). Neither the numbers nor the proliferation rates of neural stem cells in the dentate gyrus were affected by iNO. In summary, intraischemic iNO reduced neonatal HI brain injury in a gender-related manner.
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| 43. |
- Zhu, Changlian, 1964, et al.
(författare)
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Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents.
- 2010
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Ingår i: Journal of cerebral blood flow and metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 30, s. 1017-1030
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Tidskriftsartikel (refereegranskat)abstract
- Isoflurane and related anesthetics are widely used to anesthetize children, ranging from premature babies to adolescents. Concerns have been raised about the safety of these anesthetics in pediatric patients, particularly regarding possible negative effects on cognition. The purpose of this study was to investigate the effects of repeated isoflurane exposure of juvenile and mature animals on cognition and neurogenesis. Postnatal day 14 (P14) rats and mice, as well as adult (P60) rats, were anesthetized with isoflurane for 35 mins daily for four successive days. Object recognition, place learning and reversal learning as well as cell death and cytogenesis were evaluated. Object recognition and reversal learning were significantly impaired in isoflurane-treated young rats and mice, whereas adult animals were unaffected, and these deficits became more pronounced as the animals grew older. The memory deficit was paralleled by a decrease in the hippocampal stem cell pool and persistently reduced neurogenesis, subsequently causing a reduction in the number of dentate gyrus granule cell neurons in isoflurane-treated rats. There were no signs of increased cell death of progenitors or neurons in the hippocampus. These findings show a previously unknown mechanism of neurotoxicity, causing cognitive deficits in a clearly age-dependent manner.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 January 2010; doi:10.1038/jcbfm.2009.274.
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| 44. |
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| 45. |
- Zhu, Changlian, 1964, et al.
(författare)
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Nuclear translocation and calpain-dependent reduction of Bcl-2 after neonatal cerebral hypoxia-ischemia
- 2010
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Ingår i: Brain, Behavior, and Immunity. - : Elsevier BV. - 0889-1591. ; 24:5, s. 822-30
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis-related mechanisms are important in the pathophysiology of hypoxic-ischemic injury in the neonatal brain. Caspases are the major executioners of apoptosis, but there are a number of upstream players that influence the cell death pathways. The Bcl-2 family proteins are important modulators of mitochondrial permeability, working either to promote or prevent apoptosis. In this study we focused on the anti-apoptotic Bcl-2 protein after neonatal cerebral hypoxia-ischemia (HI) in 8-day-old rats. Bcl-2 translocated to nuclei and accumulated there over the first 24h of reperfusion after HI, as judged by immunohistochemistry and immuno-electron microscopy. We also found that the total level of Bcl-2 decreased after HI in vivo and after ionophore challenge in cultured human neuroblastoma (IMR-32) cells in vitro. Furthermore, the Bcl-2 reduction was calpain-dependent, because it could be prevented by the calpain inhibitor CX295 both in vivo and in vitro, suggesting cross-talk between excitotoxic and apoptotic mechanisms.
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| 46. |
- Zhu, Changlian, 1964, et al.
(författare)
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Repeated exposure of the developing rat brain to magnetic resonance imaging did not affect neurogenesis, cell death or memory function.
- 2011
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 404:1, s. 291-6
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Tidskriftsartikel (refereegranskat)abstract
- The effect of magnetic fields on the brain is a matter of debate. The objective of this study was to investigate whether repeated exposure to strong magnetic fields, such as during magnetic resonance imaging (MRI), could elicit changes in the developing rat brain. Embryonic day 15 (E15) and postnatal day 14 (P14) rats were exposed to MRI using a 7.05 T MR system. The animals were anesthetized and exposed for 35 min per day for 4 successive days. Control animals were anesthetized but no MRI was performed. Body temperature was maintained at 37°C. BrdU was injected after each session (50 mg/kg). One month later, cell proliferation, neurogenesis and astrogenesis in the dentate gyrus were evaluated, revealing no effects of MRI, neither in the E15, nor in the P14 group. DNA damage in the dentate gyrus in the P14 group was evaluated on P18, 1 day after the last session, using TUNEL staining. There was no difference in the number of TUNEL-positive cells after MRI compared with controls, neither in mature neurons, nor in newborn progenitors (BrdU/TUNEL double-labeled cells). Novel object recognition was performed to assess memory function 1 month after MRI. There was no difference in the recognition index observed after MRI compared with the control rats, neither for the E15, nor for the P14 group. In conclusion, repeated exposure to MRI did not appear to affect neurogenesis, cell death or memory function in rats, neither in late gestation (E15-E18) nor in young postnatal (P14-P17) rats.
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