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| 2. |
- 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
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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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| 3. |
- Osato, Kazuhiro, et al.
(författare)
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Carbamylated Erythropoietin Decreased Proliferation and Neurogenesis in the Subventricular Zone, but Not the Dentate Gyrus, After Irradiation to the Developing Rat Brain
- 2018
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy for pediatric brain tumors causes progressive, debilitating late effects, including cognitive decline. Erythropoietin (EPO) has been shown to be neuroprotective and to promote neuroregeneration. Carbamylated erythropoietin (CEPO) retains the protective properties of EPO but is not erythrogenic. To study the effects of CEPO on the developing brain exposed to radiotherapy, a single irradiation (IR) dose of 6Gy was administered to the brains of postnatal day 9 (P9) rats, and CEPO (40 mu g/kg s.c.) was injected on P8, P9, P11, P13, and P15. To examine proliferation, 5-Bromo-2-deoxyuridine (BrdU) was injected on P15, P16, and P17. CEPO administration did not affect BrdU incorporation in the granule cell layer (GCL) of the hippocampus or in the subventricular zone (SVZ) as quantified 7 days after the last BrdU injection, whereas IR decreased BrdU incorporation in the GCL and SVZ by 63% and 18%, respectively. CEPO did not affect BrdU incorporation in the GCL of irradiated brains, although it was reduced even further (to 31%) in the SVZ. To evaluate the effect of CEPO on neurogenesis, BrdU/doublecortin double-positive cells were quantified. CEPO did not affect neurogenesis in non-irradiated brains, whereas IR decreased neurogenesis by 58% in the dentate gyrus (DG) but did not affect it in the SVZ. In the DG, CEPO did not affect the rate of neurogenesis following IR, whereas in the SVZ, the rate decreased by 30% following IR compared with the rate in vehicle-treated rats. Neither CEPO nor IR changed the number of microglia. In summary, CEPO did not promote neurogenesis in non-irradiated or irradiated rat brains and even aggravated the decreased neurogenesis in the SVZ. This raises concerns regarding the use of EPO-related compounds following radiotherapy.
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| 4. |
- Sato, Yoshiaki, 1971, et al.
(författare)
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Grafting Neural Stem and Progenitor Cells Into the Hippocampus of Juvenile, Irradiated Mice Normalizes Behavior Deficits
- 2018
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus of the hippocampus is reduced by ionizing radiation. This explains, at least partly, the learning deficits observed in patients after radiotherapy, particularly in pediatric cases. An 8 Gy single irradiation dose was delivered to the whole brains of postnatal day 9 (P9) C57BL/6 mice, and BrdU-labeled, syngeneic NSPCs (1.0 x 10(5 )cells/injection) were grafted into each hippocampus on P21. Three months later, behavior tests were performed. Irradiation impaired novelty-induced exploration, place learning, reversal learning, and sugar preference, and it altered the movement pattern. Grafting of NSPCs ameliorated or even normalized the observed deficits. Less than 4% of grafted cells survived and were found in the dentate gyrus 5 months later. The irradiation-induced loss of endogenous, undifferentiated NSPCs in the dentate gyrus was completely restored by grafted NSPCs in the dorsal, but not the ventral, blade. The grafted NSPCs did not exert appreciable effects on the endogenous NSPCs; however, more than half of the grafted NSPCs differentiated. These results point to novel strategies aimed at ameliorating the debilitating late effects of cranial radiotherapy, particularly in children.
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| 5. |
- 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
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Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 4
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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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