Abstract
BackgroundPrimary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. Colony-stimulating factor 1 receptor (CSF-1R) signaling is essential for the survival and differentiation of microglia and monocytes. Here, we tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation.MethodsYoung adult C57BL/6J mice were given three fractions of 3.3 Gy whole-brain irradiation while they were on diet supplemented with PLX5622, and the effects on periphery monocyte accumulation, microglia numbers, and neuronal functions were assessed.ResultsThe mice developed hippocampal-dependent cognitive deficits at 1 and 3 months after they received fractionated whole-brain irradiation. The impaired cognitive function correlated with increased number of periphery monocyte accumulation in the CNS and decreased dendritic spine density in hippocampal granule neurons. PLX5622 treatment caused temporary reduction of microglia numbers, inhibited monocyte accumulation in the brain, and prevented radiation-induced cognitive deficits.ConclusionsBlockade of CSF-1R by PLX5622 prevents fractionated whole-brain irradiation-induced memory deficits. Therapeutic targeting of CSF-1R may provide a new avenue for protection from radiation-induced memory deficits.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0671-y) contains supplementary material, which is available to authorized users.
Highlights
Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation
We demonstrated an increase of monocyte accumulation in the brain, as well as a decrease of microglia, 7 days following a single dose of 10 Gy Whole-brain irradiation (WBI) [5]
There were no significant changes in Ly6Clow monocytes or neutrophils (Additional file 5: Figure S4A and B). These results suggest that the Ly6Chigh-expressing monocytes are susceptible to Colony-stimulating factor 1 receptor (CSF-1R) blockade while the Ly6Clowexpressing monocytes are not affected
Summary
Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. We tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation. Most patients with primary brain tumors are treated to a total dose of 55–60 Gy delivered in 25–30 fractions. A variety of conformal strategies are used to reduce dose to remote areas of the brain This contrasts with a total dose of 18–20 Gy used for CNS treatment of children with leukemia. Improving the quality of life of the growing population of patients who have received radiation treatment is an important objective
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