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Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum

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ABSTRACT

Posterior fossa tumors are the most common childhood intracranial tumors, and radiotherapy is one of the most effective treatments. However, irradiation induces long-term adverse effects that can have significant negative impacts on the patient’s quality of life. The purpose of this study was to characterize irradiation-induced cellular and molecular changes in the cerebellum. We found that irradiation-induced cell death occurred mainly in the external germinal layer (EGL) of the juvenile rat cerebellum. The number of proliferating cells in the EGL decreased, and 82.9% of them died within 24 h after irradiation. Furthermore, irradiation induced oxidative stress, microglia accumulation, and inflammation in the cerebellum. Interestingly, blood-brain barrier damage and blood flow reduction was considerably more pronounced in the cerebellum compared to other brain regions. The cerebellar volume decreased by 39% and the migration of proliferating cells to the internal granule layer decreased by 87.5% at 16 weeks after irradiation. In the light of recent studies demonstrating that the cerebellum is important not only for motor functions, but also for cognition, and since treatment of posterior fossa tumors in children typically results in debilitating cognitive deficits, this differential susceptibility of the cerebellum to irradiation should be taken into consideration for future protective strategies.

No MeSH data available.


Irradiation-induced newborn cell death.(A) Representative folia of the cellular layers in the juvenile cerebellum. (B) Representative BrdU staining in the EGL of the cerebellum. (C) Quantification of BrdU-labeled cells showed no difference at 6 h, but the numbers were reduced by 82.9% at 24 h after irradiation compared to the controls. (D) Representative BrdU and TUNEL double labeling in the EGL of the cerebellum. (E) Confocal quantitative analysis of BrdU and TUNEL double-positive cells. n = 4 for control and n = 6 for irradiated. EGL: external germinal layer; ML: molecular layer; PCL: Purkinje cell layer; IGL: internal granule layer; WM: white matter. ***p < 0.001.
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f2: Irradiation-induced newborn cell death.(A) Representative folia of the cellular layers in the juvenile cerebellum. (B) Representative BrdU staining in the EGL of the cerebellum. (C) Quantification of BrdU-labeled cells showed no difference at 6 h, but the numbers were reduced by 82.9% at 24 h after irradiation compared to the controls. (D) Representative BrdU and TUNEL double labeling in the EGL of the cerebellum. (E) Confocal quantitative analysis of BrdU and TUNEL double-positive cells. n = 4 for control and n = 6 for irradiated. EGL: external germinal layer; ML: molecular layer; PCL: Purkinje cell layer; IGL: internal granule layer; WM: white matter. ***p < 0.001.

Mentions: Cell proliferation in the cerebellum of the juvenile brain occurs mainly in the cerebellar EGL15 (Fig. 2A), which was measured by BrdU injection followed by BrdU immunostaining (Fig. 2B). The number of BrdU-labeled cells in the EGL was not different between control and irradiated animals at 6 h after irradiation but was reduced by 82.9% at 24 h after irradiation compared with non-irradiated controls (Fig. 2C). Cell death of these newborn cells was visualized by BrdU and TUNEL double-labeling (Fig. 2D), and quantification performed by confocal microscopy showed very few double-labeled cells in control brains, while most of the BrdU-labeled cells were TUNEL-positive at both 6 h (82.2%) and 24 h (91.7%) after irradiation (Fig. 2E).


Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum
Irradiation-induced newborn cell death.(A) Representative folia of the cellular layers in the juvenile cerebellum. (B) Representative BrdU staining in the EGL of the cerebellum. (C) Quantification of BrdU-labeled cells showed no difference at 6 h, but the numbers were reduced by 82.9% at 24 h after irradiation compared to the controls. (D) Representative BrdU and TUNEL double labeling in the EGL of the cerebellum. (E) Confocal quantitative analysis of BrdU and TUNEL double-positive cells. n = 4 for control and n = 6 for irradiated. EGL: external germinal layer; ML: molecular layer; PCL: Purkinje cell layer; IGL: internal granule layer; WM: white matter. ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5382769&req=5

f2: Irradiation-induced newborn cell death.(A) Representative folia of the cellular layers in the juvenile cerebellum. (B) Representative BrdU staining in the EGL of the cerebellum. (C) Quantification of BrdU-labeled cells showed no difference at 6 h, but the numbers were reduced by 82.9% at 24 h after irradiation compared to the controls. (D) Representative BrdU and TUNEL double labeling in the EGL of the cerebellum. (E) Confocal quantitative analysis of BrdU and TUNEL double-positive cells. n = 4 for control and n = 6 for irradiated. EGL: external germinal layer; ML: molecular layer; PCL: Purkinje cell layer; IGL: internal granule layer; WM: white matter. ***p < 0.001.
Mentions: Cell proliferation in the cerebellum of the juvenile brain occurs mainly in the cerebellar EGL15 (Fig. 2A), which was measured by BrdU injection followed by BrdU immunostaining (Fig. 2B). The number of BrdU-labeled cells in the EGL was not different between control and irradiated animals at 6 h after irradiation but was reduced by 82.9% at 24 h after irradiation compared with non-irradiated controls (Fig. 2C). Cell death of these newborn cells was visualized by BrdU and TUNEL double-labeling (Fig. 2D), and quantification performed by confocal microscopy showed very few double-labeled cells in control brains, while most of the BrdU-labeled cells were TUNEL-positive at both 6 h (82.2%) and 24 h (91.7%) after irradiation (Fig. 2E).

View Article: PubMed Central - PubMed

ABSTRACT

Posterior fossa tumors are the most common childhood intracranial tumors, and radiotherapy is one of the most effective treatments. However, irradiation induces long-term adverse effects that can have significant negative impacts on the patient&rsquo;s quality of life. The purpose of this study was to characterize irradiation-induced cellular and molecular changes in the cerebellum. We found that irradiation-induced cell death occurred mainly in the external germinal layer (EGL) of the juvenile rat cerebellum. The number of proliferating cells in the EGL decreased, and 82.9% of them died within 24&thinsp;h after irradiation. Furthermore, irradiation induced oxidative stress, microglia accumulation, and inflammation in the cerebellum. Interestingly, blood-brain barrier damage and blood flow reduction was considerably more pronounced in the cerebellum compared to other brain regions. The cerebellar volume decreased by 39% and the migration of proliferating cells to the internal granule layer decreased by 87.5% at 16 weeks after irradiation. In the light of recent studies demonstrating that the cerebellum is important not only for motor functions, but also for cognition, and since treatment of posterior fossa tumors in children typically results in debilitating cognitive deficits, this differential susceptibility of the cerebellum to irradiation should be taken into consideration for future protective strategies.

No MeSH data available.