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THE ANTI-INFLAMMATORY AND PRO-NEUROGENIC ROLE OF PPARα IN MODULATING RADIATION-INDUCED BRAIN INJURY

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abstract
Whole-brain irradiation (WBI) can lead to cognitive impairment several months to years after irradiation. At present, there are neither long-term treatments nor any preventive strategies for this significant radiation-induced late-effect. Previous studies indicate that WBI leads to impairments in hippocampal-dependent spatial learning and memory that are associated with neuro-inflammation characterized by an increase in the number of activated microglia. Preserving hippocampal neurogenesis and inhibiting microglial activation following WBI represent key strategies to minimize WBI-induced morbidity. Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that possess anti-inflammatory properties. We hypothesize that activation of PPARα will prevent radiation-induced brain injury, in part, by inhibiting the radiation-induced inflammatory responses in the microglia and by preventing the WBI-induced decrease in hippocampal neurogenesis. For our in vitro studies, we hypothesized that pre-treatment with PPARα agonists would ameliorate the pro-inflammatory responses seen in the microglia following irradiation. Irradiating BV-2 cells (a murine microglial cell line) with single doses (2-10 Gy) of 137Cs γ-rays lead to increases in 1] the gene expression of IL-1β and TNFα, 2] Cox-2 protein levels and 3] intracellular ROS generation. In addition, an increase in the DNA-binding activity of the redox-regulated pro-inflammatory transcription factors AP-1 and NF-κB was observed. Pre-treating BV-2 cells with the PPARα agonists, GW7647 and Fenofibrate significantly inhibited the radiation-induced microglial pro-inflammatory response, in part, via decreasing i] the nuclear translocation of the NF-κB p65 subunit and ii] phosphorylation of the c-jun subunit of AP-1 in the nucleus. Taken together, these data support the hypothesis that activation of PPARα can modulate the radiation-induced microglial pro-inflammatory response in vitro. In order to determine whether PPARα activation can prevent/modulate radiation-induced brain injury in vivo, we hypothesized that the PPARα agonist, fenofibrate, would prevent the WBI-mediated decrease in hippocampal neurogenesis, in part, by inhibiting microglial activation. WBI (10 Gy of 137Cs γ rays) of 129S1/SvImJ wild-type (WT) mice lead to a significant decrease in the number of newborn hippocampal neurons (BrdU+/ NeuN+) 2 months post-WBI. Fenofibrate prevented this WBI-mediated decrease in neurogenesis by promoting the survival of newborn cells in the granule cell layer/sub-granular zone. The improved neurogenesis following fenofibrate treatment was associated with decreased microglial activation in the dentate gyrus following WBI. Moreover, the neuroprotective effects of fenofibrate were abolished in PPARα knock-out mice, indicating a PPARα-dependent mechanism(s). These data highlight a novel role for PPARα ligands in improving neurogenesis following WBI, and offer the promise of improving the quality of life for brain cancer patients receiving radiotherapy.
subject
brain
neurogenesis
microglia
PPAR
ionizing radiation
inflammation
contributor
Ramanan, Sriram (author)
David Riddle (committee chair)
Mike Robbins (committee member)
Steven Kridel (committee member)
Alan Townsend (committee member)
Carol Milligan (committee member)
date
2009-04-20T16:16:44Z (accessioned)
2010-06-18T19:00:04Z (accessioned)
2009-04-20T16:16:44Z (available)
2010-06-18T19:00:04Z (available)
2009-04-20T16:16:44Z (issued)
degree
Cancer Biology (discipline)
identifier
http://hdl.handle.net/10339/14919 (uri)
language
en_US (iso)
publisher
Wake Forest University
rights
Release the entire work immediately for access worldwide. (accessRights)
title
THE ANTI-INFLAMMATORY AND PRO-NEUROGENIC ROLE OF PPARα IN MODULATING RADIATION-INDUCED BRAIN INJURY
type
Dissertation

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