The PPARalpha Agonist Fenofibrate Preserves Hippocampal Neurogenesis and Inhibits Microglial Activation After Whole-Brain Irradiation

Journal Article · Sun Nov 01 00:00:00 EDT 2009 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2009.06.059· OSTI ID:21362227

Ramanan, Sriram ^[1]; Kooshki, Mitra; Weiling, Zhao ^[2]; Hsu, F -C ^[3]; Riddle, David R ^[2]

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1. Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC (United States)
2. Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC (United States)
3. Department of Biostatistical Sciences, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC (United States)

Purpose: Whole-brain irradiation (WBI) leads to cognitive impairment months to years after radiation. Numerous studies suggest that decreased hippocampal neurogenesis and microglial activation are involved in the pathogenesis of WBI-induced brain injury. The goal of this study was to investigate whether administration of the peroxisomal proliferator-activated receptor (PPAR) alpha agonist fenofibrate would prevent the detrimental effect of WBI on hippocampal neurogenesis. Methods and Materials: For this study, 129S1/SvImJ wild-type and PPARalpha knockout mice that were fed either regular or 0.2% wt/wt fenofibrate-containing chow received either sham irradiation or WBI (10-Gy single dose of {sup 137}Cs gamma-rays). Mice were injected intraperitoneally with bromodeoxyuridine to label the surviving cells at 1 month after WBI, and the newborn neurons were counted at 2 months after WBI by use of bromodeoxyuridine/neuronal nuclei double immunofluorescence. Proliferation in the subgranular zone and microglial activation were measured at 1 week and 2 months after WBI by use of Ki-67 and CD68 immunohistochemistry, respectively. Results: Whole-brain irradiation led to a significant decrease in the number of newborn hippocampal neurons 2 months after it was performed. Fenofibrate prevented this decrease by promoting the survival of newborn cells in the dentate gyrus. In addition, fenofibrate treatment was associated with decreased microglial activation in the dentate gyrus after WBI. The neuroprotective effects of fenofibrate were abolished in the knockout mice, indicating a PPARalpha-dependent mechanism or mechanisms. Conclusions: These data highlight a novel role for PPARalpha ligands in improving neurogenesis after WBI and offer the promise of improving the quality of life for brain cancer patients receiving radiotherapy.

• OSTI ID: 21362227
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 75, Issue 3; Other Information: DOI: 10.1016/j.ijrobp.2009.06.059; PII: S0360-3016(09)01017-7; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
CESIUM 137
GAMMA RADIATION
HIPPOCAMPUS
INJURIES
IRRADIATION
KNOCK-OUT REACTIONS
MICE
NEOPLASMS
NERVE CELLS
PATHOGENESIS
RADIOTHERAPY
RECEPTORS
ANIMAL CELLS
ANIMALS
BETA DECAY RADIOISOTOPES
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CENTRAL NERVOUS SYSTEM
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DIRECT REACTIONS
DISEASES
ELECTROMAGNETIC RADIATION
INTERMEDIATE MASS NUCLEI
IONIZING RADIATIONS
ISOTOPES
MAMMALS
MEDICINE
MEMBRANE PROTEINS
NERVOUS SYSTEM
NUCLEAR MEDICINE
NUCLEAR REACTIONS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANS
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