Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts via binding to a cell surface receptor named Fn14. To study the role of this cytokine in the regulation of the permeability of the neurovascular unit (NVU) during cerebral ischemia, TWEAK activity was inhibited in wild-type mice with a soluble Fn14-Fc decoy receptor administered either immediately or 1 h after middle cerebral artery occlusion (MCAO). Administration of Fn14-Fc decoy resulted in faster recovery of motor function and a 66.4%+/-10% decrease in Evans blue dye extravasation when treatment was administered immediately after MCAO and a 46.1%+/-13.1% decrease when animals were treated 1 h later (n=4, P<0.05). Genetic deficiency of Fn14 resulted in a 60%+/-12.8% decrease in the volume of the ischemic lesion (n=6, P<0.05), and a 87%+/-22% inhibition in Evans blue dye extravasation 48 h after the onset of the ischemic insult (n=6, P<0.005). Compared with control animals, treatment with Fn14-Fc decoy or genetic deficiency of Fn14 also resulted in a significant inhibition of nuclear factor-kappaB pathway activation, matrix metalloproteinase-9 activation and basement membrane laminin degradation after MCAO. These findings show that the cytokine TWEAK plays a role in the disruption of the structure of the NVU during cerebral ischemia and that TWEAK antagonism is a potential therapeutic strategy for acute cerebral ischemia.