title: The PPARδ agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation.
abstract: Brain tumor patients often develop cognitive impairment months to years after partial or fractionated whole-brain irradiation (WBI). Studies suggest that neuroinflammation and decreased hippocampal neurogenesis contribute to the pathogenesis of radiation-induced brain injury. In this study, we determined if the peroxisomal proliferator-activated receptor (PPAR) δ agonist GW0742 can prevent radiation-induced brain injury in C57Bl/6 wild-type (WT) and PPARδ knockout (KO) mice. Dietary GW0742 prevented the acute increase in IL-1β mRNA and ERK phosphorylation measured at 3h after a single 10-Gy dose of WBI; it also prevented the increase in the number of activated hippocampal microglia 1 week after WBI. In contrast, dietary GW074 failed to prevent the radiation-induced decrease in hippocampal neurogenesis determined 2 months after WBI in WT mice or to mitigate their hippocampal-dependent spatial memory impairment measured 3 months after WBI using the Barnes maze task. PPARδ KO mice exhibited defects including decreased numbers of astrocytes in the dentate gyrus/hilus of the hippocampus and a failure to exhibit a radiation-induced increase in activated hippocampal microglia. Interestingly, the number of astrocytes in the dentate gyrus/hilus was reduced in WT mice, but not in PPARδ KO mice 2 months after WBI. These results demonstrate that, although dietary GW0742 prevents the increase in inflammatory markers and hippocampal microglial activation in WT mice after WBI, it does not restore hippocampal neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after WBI. Thus, the exact relationship between radiation-induced neuroinflammation, neurogenesis, and cognitive impairment remains elusive.
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Caroline I
authors.initials: CI
authors.lastname: Schnegg
authors.affiliation: Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Electronic address: dgreenes@wakehealth.edu.
authors.forename: Dana
authors.initials: D
authors.lastname: Greene-Schloesser
authors.affiliation: Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Mitra
authors.initials: M
authors.lastname: Kooshki
authors.affiliation: Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Payne
authors.affiliation: Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Mike E
authors.initials: ME
authors.lastname: Robbins
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D016371:Cranial Irradiation / Q000009:adverse effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000502:physiology / Q000528:radiation effects*; D007249:Inflammation / Q000517:prevention & control; D053583:Interleukin-1beta / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000528:radiation effects; D055495:Neurogenesis / Q000187:drug effects*; D047494:PPAR delta / Q000819:agonists*; D010766:Phosphorylation; D013844:Thiazoles / Q000494:pharmacology*; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D053583:Interleukin-1beta; D047494:PPAR delta; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: C57Bl/6 wild-type mice; Cognitive impairment; Free radicals; Neurogenesis; Neuroinflammation; PPARδ KO mice; PPARδ agonists; Whole-brain irradiation