Sex differences and the role of PPAR alpha in experimental stroke

Males and females respond differently to stroke. Moreover, females often experience worse long-term stroke outcomes. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist has been shown to improve stroke outcome and resolve neuroinflammation in male mice. The present study compares the effect of pretreatment with fenofibrate versus vehicle control in male and female mice during experimental stroke. Mice were treated with low-dose fenofibrate 30 min before and once a day for three additional days after stroke onset. We observed a reduction in infarct volume in male mice 96 h post-stroke with low-dose fenofibrate pretreatment that was due to increase of an M2 macrophage phenotype in the brain and an increase in regulatory cells in the periphery. These outcomes were not replicated in females, likely due to the lower PPARα expression in cells and tissues in females vs males. We conclude that PPARα agonist treatment prior to stroke is neuroprotective in males but not females. These findings indicate PPARα as a probable mechanism of sex difference in stroke outcome and support the need for representation of females in stroke therapy research.