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Adropin has been shown to improve peripheral endothelial dysfunction, reduce insulin resistance, and increase glucose utilization in obesity and diabetes. Although we showed that adropin reduces paracellular permeability of brain endothelial cells exposed to ischemia-like conditions, little is known of the effects of adropin in the brain. We hypothesized that adropin exerts neuroprotection through activation of endothelial nitric oxide synthase (eNOS)/NO signaling pathway and reduction of blood-brain barrier (BBB) damage. Male mice were subjected to permanent middle cerebral artery occlusion (MCAO) and treated intravenously with either vehicle or synthetic adropin (90, 900 and 2700 nmol/kg) at the onset of ischemia and sacrificed to determine infarct size at 48 h. Cellular localization of adropin was determined using immunofluorescence. Brain tissue was collected at 24 h after stroke to determine BBB damage, matrix metalloproteinase (MMP)-9 activity, and levels of tight junction proteins, eNOS, and gp91phox-containing NADPH oxidase. We determined the effects of a 3-h delayed administration on stroke outcomes to evaluate the translational value of adropin therapy. In the brain, adropin was expressed on endothelial cells and at a low level on astrocytes after stroke. Adropin given at the onset of MCAO dose-dependently reduced infarct size. More importantly, delaying adropin administration to 3 h post-MCAO profoundly reduced infarct size compared to vehicle-treated mice. Ischemia slightly increased eNOS phosphorylation at Ser1176, significantly increased gp91phox (a major source of reactive oxygen species), and reduced brain adropin levels. Adropin treatment induced a dramatic increase in eNOS phosphorylation, significantly reduced gp91phox levels, and restored endogenous adropin levels compared to the vehicle group. Additionally, adropin protected against a stroke-induced increase in MMP-9 activity, loss of zona occludens-1 and occludin, and BBB disruption as assessed by extravasated IgG and albumin. Collectively, these findings indicate that adropin-mediated neuroprotection in ischemic stroke may be through an increase in eNOS-derived NO bioavailability, reduction of gp91phox, and decreased MMP-9 activity and BBB damage.