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- Kalm, Marie, 1981
(författare)
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Inflammation and behavior following irradiation-induced injury in the developing brain
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Radiotherapy is used in the treatment of pediatric brain tumors and is often associated with debilitating late effects, such as intellectual impairment. Areas in the brain harboring stem cells are particularly sensitive to irradiation (IR) and loss of these cells may contribute to cognitive deficits. It has been demonstrated that IR-induced inflammation negatively affects neural progenitor differentiation. Therefore, it is necessary to investigate the inflammatory mechanism to be able to find potential treatment strategies. One moderate dose of IR to the young rodent brain caused injuries that were detectable after several months, including impaired growth. We have shown that IR to the developing brain induces an acute inflammatory response. An unexpected finding was that microglia died shortly after treatment. The consequences of IR-induced microglia loss can either be that the injury, due to pronounced inflammation, is decreased, or that injury is enhanced due to weakened repair mechanisms. Further investigations are needed to elucidate how the loss of microglia affects the response to IR and brain development. The third complement component (C3) is a key protein of the complement system which we found to be upregulated after IR. C3 has been shown to be important for neurogenesis, and therefore we wanted to investigate the role of complement activation after IR by using C3-deficient mice. Interestingly, the IR-induced injury, measured as tissue loss and decrease of proliferating cells, was not as pronounced in the dentate gyrus of C3-deficient mice as in wild type mice. This indicates that manipulation of the complement system could be a fruitful strategy to protect the neurogenic areas from IR-induced injuries. We have studied functional consequences of IR to the growing brain. We saw that one dose of IR to the young rodent brain caused behavioral changes that were detectable months and even one year after the treatment. Furthermore, non-irradiated animals performed better than irradiated ones in different learning tasks. Importantly, months after IR C3-deficient mice made fewer errors in place learning and reversal learning tests than WT mice. These results indicate that the complement system contributes to both morphological and functional IR-induced injury in the young brain.
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| 2. |
- Kalm, Marie, 1981, et al.
(författare)
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Irradiation-induced loss of microglia in the young brain.
- 2009
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Ingår i: Journal of neuroimmunology. - : Elsevier BV. - 0165-5728. ; 206:1-2, s. 70-5
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Tidskriftsartikel (refereegranskat)abstract
- Irradiation-induced loss of neural stem and progenitor cells may contribute to cognitive deficits. Furthermore, subsequent inflammation inhibits neural progenitor cell differentiation. Here we have characterized the microglia response after a single dose of 8 Gy to the brains of postnatal day 9 or 21 rats. The number of Iba-1-positive microglia increased 6 h after IR but had decreased 7 days later, below control levels, and this decrease was more pronounced in P9 rats. Active caspase-3 and TUNEL staining revealed irradiation-induced microglia death. This age-dependent IR-induced loss of microglia likely affects both the response to IR and further brain development.
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| 3. |
- Kalm, Marie, 1981, et al.
(författare)
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Transient inflammation in neurogenic regions after irradiation of the developing brain.
- 2009
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Ingår i: Radiation research. - 0033-7587. ; 171:1, s. 66-76
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Tidskriftsartikel (refereegranskat)abstract
- Kalm, M., Fukuda, A., Fukuda, H., Ohrfelt, A., Lannering, B., Björk-Eriksson, T., Blennow, K., Márky, I. and Blomgren, K. Transient Inflammation in Neurogenic Regions after Irradiation of the Developing Brain. Radiat. Res. 171, 66-76 (2009).We characterized the inflammatory response after a single dose of 8 Gy to the brains of postnatal day 9 rats. Affymetrix gene chips revealed activation of multiple inflammatory mechanisms in the acute phase, 6 h after irradiation. In the subacute phase, 7 days after irradiation, genes related to neurogenesis and cell cycle were down-regulated, but glial fibrillary acidic protein (GFAP) was up-regulated. The concentrations of 14 different cytokines and chemokines were measured using a microsphere-based xMAPtrade mark technology. CCL2, Gro/KC and IL-1alpha were the most strongly up-regulated 6 h after irradiation. CCL2 was expressed in astrocytes and microglia in the dentate gyrus and the subventricular zone (SVZ). Hypertrophy, but not hyperplasia, of astrocytes was demonstrated 7 days after irradiation. In summary, we found transient activation of multiple inflammatory mechanisms in the acute phase (6 h) after irradiation and activation of astrocytes in the subacute phase (7 days) after irradiation. It remains to be elucidated whether these transient changes are involved in the persistent effects of radiation observed on neurogenesis and cognition in rodents.
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