Abstract
INTRODUCTION
Fractionated whole brain irradiation is widely used for the treatment of primary brain tumors and brain metastases. Long-term survival occurs depending on the tumor type, but patients often develop cognitive deficits after radiation. The underlying mechanisms that cause loss of cognitive function after radiotherapy are not clear, and there is no treatment available to prevent the adverse effects. We have previously reported that temporary depletion of microglia by CSF-1R inhibition protects neuronal structures and prevents fractionated whole brain irradiation (WBI) induced memory loss in mice.
METHODS
Here, we established a novel glioma model by engineered rodent glioma cell line GL261 to express diphtheria toxin receptor (DTR) in mice. This model allows restriction of tumor growth/progression after treatment with diphtheria toxin (DT) and assessment of cognitive functions. We simulate the effect of tumor growth with subsequent fractionated radiation treatment, and tested the outcomes of CSF-1R antagonist treatment during radiotherapy on cognitive function.
RESULTS
We found that 1) DT treatment significantly prolonged survival of glioma bearing mice; 2) Tumor growth and DT treatment did not affect object recognition memory; 3) Radiotherapy further prolonged survival of glioma bearing mice but resulted in memory deficits; and 4) CSF-1R inhibition during radiotherapy prevented fractionated whole brain irradiation-induced memory loss.
CONCLUSIONS
These results suggest that 1) WBI, not tumor growth, is the main cause of memory impairment in glioma bearing mice; and 2) transient CSF-1R inhibition during radiotherapy could prevent cognitive decline in patients.