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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.


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Irradiation increased blood-brain barrier (BBB) permeability and decreased blood flow in the cerebellum.(A) Representative albumin immunostaining in the cerebellum for control and irradiated animals at 24 hours post irradiation (top panel). (B) Albumin density in the cerebellum increased significantly at 6 h and 24 h after irradiation (n = 8/group). (C) Blood flow was decreased significantly in all the measured brain regions except in the brain stem at 6 h after irradiation. The reduction was most pronounced in the cerebellum (n = 9/group). Hippocampus: Hip; Cerebellum: Cb; Cortex: Cx; Brain stem: BS; Striatum/thalamus: ST. *p < 0.05, **p < 0.01.
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f5: Irradiation increased blood-brain barrier (BBB) permeability and decreased blood flow in the cerebellum.(A) Representative albumin immunostaining in the cerebellum for control and irradiated animals at 24 hours post irradiation (top panel). (B) Albumin density in the cerebellum increased significantly at 6 h and 24 h after irradiation (n = 8/group). (C) Blood flow was decreased significantly in all the measured brain regions except in the brain stem at 6 h after irradiation. The reduction was most pronounced in the cerebellum (n = 9/group). Hippocampus: Hip; Cerebellum: Cb; Cortex: Cx; Brain stem: BS; Striatum/thalamus: ST. *p < 0.05, **p < 0.01.

Mentions: BBB permeability was determined by albumin immunoreactivity in the extravascular tissue. Increased albumin staining was observed in the cerebellum of irradiated brains, but neither in control brains nor in any other brain regions after irradiation (Fig. 5A). The albumin positive staining increased significantly in the cerebellum as early as 6 h and persisted up to 24 h after irradiation (Fig. 5B). Cerebral blood flow (CBF) was assessed by the iodoantipyrine method in different brain regions and CBF significantly decreased at 6 h after irradiation in all measured brain regions, although not significantly so in the brain stem. The decrease in CBF was most pronounced in the cerebellum (53.7% reduction, p = 0.0003) compared to the cortex (31.4% reduction, p = 0.0213), hippocampus (29.1% reduction, p = 0.0414), brain stem (29% reduction, p = 0.0619), and the striatum/thalamus (29.9% reduction, p = 0.0394) (Fig. 5C).


Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum
Irradiation increased blood-brain barrier (BBB) permeability and decreased blood flow in the cerebellum.(A) Representative albumin immunostaining in the cerebellum for control and irradiated animals at 24 hours post irradiation (top panel). (B) Albumin density in the cerebellum increased significantly at 6 h and 24 h after irradiation (n = 8/group). (C) Blood flow was decreased significantly in all the measured brain regions except in the brain stem at 6 h after irradiation. The reduction was most pronounced in the cerebellum (n = 9/group). Hippocampus: Hip; Cerebellum: Cb; Cortex: Cx; Brain stem: BS; Striatum/thalamus: ST. *p < 0.05, **p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382769&req=5

f5: Irradiation increased blood-brain barrier (BBB) permeability and decreased blood flow in the cerebellum.(A) Representative albumin immunostaining in the cerebellum for control and irradiated animals at 24 hours post irradiation (top panel). (B) Albumin density in the cerebellum increased significantly at 6 h and 24 h after irradiation (n = 8/group). (C) Blood flow was decreased significantly in all the measured brain regions except in the brain stem at 6 h after irradiation. The reduction was most pronounced in the cerebellum (n = 9/group). Hippocampus: Hip; Cerebellum: Cb; Cortex: Cx; Brain stem: BS; Striatum/thalamus: ST. *p < 0.05, **p < 0.01.
Mentions: BBB permeability was determined by albumin immunoreactivity in the extravascular tissue. Increased albumin staining was observed in the cerebellum of irradiated brains, but neither in control brains nor in any other brain regions after irradiation (Fig. 5A). The albumin positive staining increased significantly in the cerebellum as early as 6 h and persisted up to 24 h after irradiation (Fig. 5B). Cerebral blood flow (CBF) was assessed by the iodoantipyrine method in different brain regions and CBF significantly decreased at 6 h after irradiation in all measured brain regions, although not significantly so in the brain stem. The decrease in CBF was most pronounced in the cerebellum (53.7% reduction, p = 0.0003) compared to the cortex (31.4% reduction, p = 0.0213), hippocampus (29.1% reduction, p = 0.0414), brain stem (29% reduction, p = 0.0619), and the striatum/thalamus (29.9% reduction, p = 0.0394) (Fig. 5C).

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.


Related in: MedlinePlus