PPARα ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways

Whole-brain irradiation (WBI) can lead to cognitive impairment several months to years after irradiation. Studies on rodents have shown a rapid and sustained increase in activated microglia (brain macrophages) following brain irradiation, contributing to a chronic inflammatory response and a corresponding decrease in hippocampal neurogenesis. Thus, alleviating microglial activation following radiation represents a key strategy to minimize WBI-induced morbidity. We hypothesized that pretreatment with peroxisomal proliferator-activated receptor (PPAR)α agonists would ameliorate the proinflammatory responses seen in the microglia following in vitro radiation. Irradiating BV-2 cells (a murine microglial cell line) with single doses (2–10 Gy) of 137Cs γ-rays led 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 redox-regulated proinflammatory transcription factors AP-1 and NF-κB was observed. Pretreating BV-2 cells with the PPARα agonists GW7647 and Fenofibrate significantly inhibited the radiation-induced microglial proinflammatory 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 proinflammatory response.