Fenofibrate alleviates the brain edema after traumatic brain injury by enhancing endothelial OXPHOS.

Traumatic brain injury (TBI) frequently leads to brain edema, a life-threatening complication and a major cause of mortality and disability. Here, we report that fenofibrate (FFB), an agonist of the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα), alleviates post-traumatic brain edema by enhancing blood-brain barrier (BBB) integrity in a mouse model of severe TBI. Mechanistic studies in cultured endothelial cells and endothelial-specific PPARα conditional knockout mice revealed that FFB activates PPARα, enhances mitochondrial oxidative phosphorylation (OXPHOS), and thereby reduces oxidative stress and endothelial cell apoptosis. These findings identify PPARα-dependent enhancement of energy metabolism in the brain endothelium as a promising therapeutic strategy for TBI-induced edema.