ABSTRACT
Ionizing radiation (IR) is commonly used to treat central nervous system (CNS) cancers and metastases. While IR promotes remission, frequent side effects including impaired cognition and white matter loss occur following treatment. Fractionation is used to minimize these CNS late side effects, as it reduces IR effects in differentiated normal tissue, but not rapidly proliferating normal or tumor tissue. However, side effects occur even with the use of fractionated paradigms. Oligodendrocyte progenitor cells (OPCs) are a proliferative population within the CNS affected by radiation. We hypothesized that fractionated radiation would lead to OPC loss, which could contribute to the delayed white matter loss seen after radiation exposure. We found that fractionated IR induced a greater early loss of OPCs than an equivalent single dose exposure. Furthermore, OPC recovery was impaired following fractionated IR. Finally, reduced OPC differentiation and mature oligodendrocyte numbers occurred in single dose and fractionated IR paradigms. This work demonstrates that fractionation does not spare normal brain tissue and, importantly, highlights the sensitivity of OPCs to fractionated IR, suggesting that fractionated schedules may promote white matter dysfunction, a point that should be considered in radiotherapy.
Subject(s)
Dose Fractionation, Radiation , Oligodendrocyte Precursor Cells/radiation effects , Radiation Tolerance , Animals , Antineoplastic Agents, Hormonal/pharmacology , Apoptosis/drug effects , Apoptosis/radiation effects , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain/radiation effects , Bromodeoxyuridine , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cesium Radioisotopes , Dose-Response Relationship, Drug , Female , Glutathione S-Transferase pi/genetics , Glutathione S-Transferase pi/metabolism , Immunohistochemistry , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Mice, Transgenic , Oligodendrocyte Precursor Cells/drug effects , Oligodendrocyte Precursor Cells/metabolism , Oligodendrocyte Precursor Cells/pathology , Radiation Tolerance/drug effects , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Recovery of Function , Sex Characteristics , Tamoxifen/pharmacologyABSTRACT
PURPOSE: To determine the late effects of fractionated versus single-dose cranial radiation on murine white matter. METHODS AND MATERIALS: Mice were exposed to 0 Gy, 6 × 6 Gy, or 1 × 20 Gy cranial irradiation at 10 to 12 weeks of age. Endpoints were assessed through 18 months from exposure using immunohistochemistry, electron microscopy, and electrophysiology. RESULTS: Weight gain was temporarily reduced after irradiation; greater loss was seen after single versus fractionated doses. Oligodendrocyte progenitor cells were reduced early and late after both single and fractionated irradiation. Both protocols also increased myelin g-ratio, reduced the number of nodes of Ranvier, and promoted a shift in the proportion of small, unmyelinated versus large, myelinated axon fibers. CONCLUSIONS: Fractionation does not adequately spare normal white matter from late radiation side effects.
