International Journal of Radiation Oncology*Biology*Physics
Biology ContributionThe PPARα Agonist Fenofibrate Preserves Hippocampal Neurogenesis and Inhibits Microglial Activation After Whole-Brain Irradiation
Introduction
Brain metastases will develop in up to 30% of the approximately 1.5 million new cancer patients estimated in the United States in 2009 1, 2. Large-field partial or whole-brain irradiation (WBI) is the primary mode of treatment for brain metastases; approximately 170,000 patients are treated annually with cranial irradiation (3). Unfortunately, progressive, cognitive impairment will develop in up to 50% of brain tumor patients who survive for 6 months or more after irradiation (4). This cognitive dysfunction is evident often as deficits in hippocampal-dependent learning and memory, including spatial information processing 4, 5. Moreover, it has been suggested that the severity of cognitive impairment correlates with the radiation dose delivered to the medial temporal lobe, the site of the hippocampus (6).
The exact mechanisms involved in the development and progression of radiation-induced brain injury are unknown. However, studies on both rodents and human tissue samples indicate that WBI has a detrimental effect on hippocampal neurogenesis 7, 8. Active neurogenesis occurs throughout adulthood in a specialized region of the hippocampus called the dentate gyrus (DG) (9). Neural precursor cells residing in the subgranular zone (SGZ) of the DG give rise to new neurons that functionally integrate into the granule cell layer (GCL) of the hippocampus (10). The extreme sensitivity of these neural precursor cells to irradiation has been shown previously 7, 11, 12. Irradiation of the rodent brain leads to a marked decrease in the number of newborn mature and immature neurons in the DG, associated with impairments in hippocampal-dependent cognitive tasks 13, 14. This WBI-induced decrease in neurogenesis has been linked with neuroinflammation, as evidenced by a marked increase in the number of activated microglia 7, 14. Specifically, inhibiting microglial activation by use of indomethacin and minocycline partially restores neurogenesis 15, 16. Thus anti-inflammatory strategies might be effective in preserving hippocampal neurogenesis and ameliorating radiation-induced cognitive impairment.
Peroxisomal proliferator-activated receptor (PPAR) α is a nuclear receptor belonging to the PPAR family of ligand-activated transcription factors (17). It has been shown to play a major role in regulating inflammatory processes. In vitro PPARα agonists inhibit proinflammatory responses in a variety of cell types, including microglia and astrocytes (18). Moreover, PPARα agonists confer neuroprotection in a variety of preclinical models, including stroke, experimental autoimmune encephalomyelitis, and Parkinson's disease (19). We previously reported that pretreating BV-2 murine microglial cells with the PPARα agonist fenofibrate inhibited the radiation-induced proinflammatory response, via negative regulation of NF-κB and AP-1 pathways (20). We hypothesized in this study that fenofibrate would ameliorate the WBI-induced decrease in hippocampal neurogenesis, in part, by inhibiting microglial activation.
Section snippets
Animals and irradiation procedures
Adult (12–16 weeks old) PPARα knockout (KO) mice (129S4/ScJac-Pparatm/Gonz [Stock No. 003580]; The Jackson Laboratory, Bar Harbor, MN) and their appropriate wild-type (WT) controls (129S1/SvImJ [Stock No. 002448]; The Jackson Laboratory) were housed in specific pathogen-free conditions, with 5 mice per cage with free access to drinking water and standard mouse chow (Harlan Teklad, Madison, WI). All animal handling and experiments were performed in strict accordance with the National Institutes
Fenofibrate inhibited WBI-induced decrease in newborn neurons in hippocampus, affecting cell survival but not proliferation
Given the neuroprotective role of PPARα ligands in other models of brain injury, we hypothesized that fenofibrate administration would prevent the deleterious effect of WBI on hippocampal neurogenesis. As shown in Fig. 1A, the WT control diet mice showed a 60% reduction in the number of BrdU+/NeuN+ cells in the GCL/SGZ at 2 months after WBI. This radiation-induced decrease in newborn neurons was prevented in the mice that received fenofibrate.
Extending previous studies (12), we found that WBI
Discussion
The central finding of this study is that dietary administration of the PPARα ligand fenofibrate preserves the number of newborn hippocampal neurons and decreases microglial activation after WBI in WT mice. These protective effects are not observed in PPARα KO mice, highlighting the importance of this nuclear receptor in mediating the action of fenofibrate. To our knowledge, this is the first demonstration of a role for PPARα in modulating adult hippocampal neurogenesis after WBI.
Hippocampal
Acknowledgments
We thank Dr. Kelly Conner, Dr. Matthew Schindler, Liz Forbes, and Dr. Kun Hua (Department of Neurobiology and Anatomy, Wake Forest University School of Medicine) for providing technical assistance with immunohistochemistry and microscopy.
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Supported by National Institutes of Health grants CA112593 (M.E.R.) and AG11370 (D.R.R.).
Conflict of interest: none.