Fractionated partial or whole-brain irradiation (fWBI) is often required to treat both primary and metastatic brain cancer. Radiation-induced brain injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year [68, 69]. Recent reports indicate that the pathogenesis of radiation-induced brain injury may be caused, in part, by chronic oxidative stress and inflammatory responses, as well as increased microglial activation in the brain [70–72]. Microglia, which are termed the macrophages of the brain, are considered to be one of the key mediators of neuroinflammation [73–75]. Data suggest that irradiating microglial cells in vitro leads to an increase in a variety of proinflammatory mediators, including the cytokines, TNF-α and IL-1β, and the chemokines, MCP-1 and ICAM-1 [76–78]. Studies performed in vivo indicate that there is an increase in proinflammatory mediators within hours of irradiating the rodent brain [76, 79]. To date, studies in rodents have demonstrated that administration of anti-inflammatory drugs can decrease radiation-induced microglial activation [80, 81]. These findings provide a strong rationale for investigating whether administration of PPARδ agonists can confer neuroprotection following irradiation.
