The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation.
OBJECTIVE
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
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 (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.
Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Sriram
S
Ramanan
Mitra
M
Kooshki
Weiling
W
Zhao
Fang-Chi
FC
Hsu
David R
DR
Riddle
Mike E
ME
Robbins
D000818:Animals; D001921:Brain / Q000528:radiation effects; D001973:Bromodeoxyuridine / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D016371:Cranial Irradiation / Q000009:adverse effects*; D011345:Fenofibrate / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000528:radiation effects; D055495:Neurogenesis / Q000187:drug effects* / Q000528:radiation effects; D047493:PPAR alpha / Q000819:agonists*; D011837:Radiation-Protective Agents / Q000494:pharmacology
D047493:PPAR alpha; D011837:Radiation-Protective Agents; D001973:Bromodeoxyuridine; D011345:Fenofibrate