The Peroxisomal Proliferator-Activated Receptor (PPAR) α Agonist, Fenofibrate, Prevents Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment

Abstract

We hypothesized that dietary administration of the peroxisomal proliferator-activated receptor α agonist, fenofibrate, to young adult male rats would prevent the fractionated whole-brain irradiation (fWBI)-induced reduction in cognitive function and neurogenesis and prevent the fWBI-induced increase in the total number of activated microglia. Eighty 12–14-week-old young adult male Fischer 344 × Brown Norway rats received either: (1) sham irradiation, (2) 40 Gy of fWBI delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation + dietary fenofibrate (0.2% w/w) starting 7 days prior to irradiation, or (4) fWBI + fenofibrate. Cognitive function was measured 26–29 weeks after irradiation using: (1) the perirhinal cortex (PRh)-dependent novel object recognition task; (2) the hippocampal-dependent standard Morris water maze (MWM) task; (3) the hippocampal-dependent delayed match-to-place version of the MWM task; and (4) a cue strategy preference version of the MWM to distinguish hippocampal from striatal task performance. Neurogenesis was assessed 29 weeks after fWBI in the granular cell layer and subgranular zone of the dentate gyrus using a doublecortin antibody. Microglial activation was assessed using an ED1 antibody in the dentate gyrus and hilus of the hippocampus. A significant impairment in perirhinal cortex-dependent cognitive function was measured after fWBI. In contrast, fWBI failed to alter hippocampal-dependent cognitive function, despite a significant reduction in hippocampal neurogenesis. Continuous administration of fenofibrate prevented the fWBI-induced reduction in perirhinal cortex-dependent cognitive function, but did not prevent the radiation-induced reduction in neurogenesis or the radiation-induced increase in activated microglia. These data suggest that fenofibrate may be a promising therapeutic for the prevention of some modalities of radiation-induced cognitive impairment in brain cancer patients.

Cellular response of the rat brain to single doses of137Cs γ rays does not predict its response to prolonged ‘biologically equivalent’ fractionated doses

“…Previous studies of radiation-induced brain injury in adult rodent models have reported no change in the total number of microglia in the DG/hilus of the hippocampus at 2–3 months after a single doses of WBI (Monje et al 2002, Hua et al 2012) or 6 months after fWBI (Lee et al 2012, Greene-Schloesser et al 2014). However there are studies that have shown decreases in the total microglia population in the young adult rodent after single doses (Son et al 2014) or fWBI (Conner et al 2010).…”

“…All analyses were performed using coded sections with a Zeiss AxioImager M2, (Göttingen, Germany) equipped with a semi-automatic stereology system (StereoInvestigator software, Microbrightfield, Inc.) as previously described by us (Lee et al 2012, Greene-Schloesser et al 2014). Briefly, the optical fractionator method (Gundersen et al 1988) was used for quantification of immunolabeled cells in the granular cell layer (GCL), subgranular zone (SGZ) and hilus.…”

“…These cells then generate ROS which in turn activate more microglia that can maintain or increase the level of oxidative stress (Hanisch and Kettenmann 2007). Evidence for a chronic, radiation-induced inflammatory response in rodent models includes: (i) Elevation of inflammatory cytokines up to 6 months post-irradiation (Hong et al 1995, Lee et al 2010); (ii) a significant increase in the number of activated microglia in the dentate gyrus (DG) (Monje et al 2002, 2003, Lee et al 2012, Greene-Schloesser et al 2014); (iii) increased expression of the CCR2 receptor in the subgranular zone (Rola et al 2005); and (iv) persistent microglial and astrocyte activation (Chiang et al 1993, Schindler et al 2008). …”

“…Although microglial activation plays an important role in phagocytosis of dead cells, sustained activation is thought to contribute to a chronic inflammatory state in the brain (Gebicke-Haerter 2001, Joo et al 2012). Measurements of a chronic inflammatory brain response to single doses and fWBI in rodent models include: (i) Elevation of TNFα (Hong et al 1995); (ii) up-regulation of IL-1β (Lee et al 2010, Schnegg et al 2013); (iii) a marked increase in the percentage of activated microglia (Monje et al 2002, 2003, Lee et al 2012, Schnegg et al 2013, Greene-Schloesser et al 2014); and (iv) persistent microglial activation (Schindler et al 2008, Ramanan et al 2009, Conner et al 2010, Lee et al 2012, Greene-Schloesser et al 2014). Previous studies have also suggested that microglial activation may be associated with decreased hippocampal neurogenesis and cognitive function (Monje et al 2002, 2007, Raber et al 2004).…”

The Current Utilization of Cognitive Tests in the Research of Radiation-Induced Cognitive Dysfunction in Rodent Models

“…The spatial learning and reference memory of Sprague-Dawley rats was impaired by dosage of 40 Gy/8 f for 1 and 2 months and recovered after 3 months postirradiation [40]. At approximately 7 months post-irradiation, spatial learning and reference memory were not influenced by dosage of 40 Gy/8 f for F344xBN rats [60]. As for the dosage of 20 Gy/4 f, it increased the latency to the platform and decreased target quadrant stay time for C57BL/6J mice 2 months post-irradiation [43], but it made no difference for Sprague-Dawley rats and Wistar rats after nearly the same time interval after irradiation [40,56].…”