Platelet glycoprotein receptor Ib blockade ameliorates experimental cerebral ischemia-reperfusion injury by strengthening the blood-brain barrier function and anti-thrombo-inflammatory property

Blood-brain barrier (BBB) disruption, thrombus formation and immune-mediated inflammation are important steps in the pathophysiology of cerebral ischemia-reperfusion injury but are still inaccessible to therapeutic interventions. Recent studies have provided increasing evidence that blocking of platelet glycoprotein (GP) receptor Ib might represent a novel target in treating acute ischemic stroke. This research was conducted to explore the therapeutic efficacy and potential mechanisms of GPIbα inhibitor (anfibatide) in a model of brain ischemia-reperfusion injury in mice. Male mice underwent 90 min of right middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Anfibatide (1, 2, 4 ug/kg) or tirofiban were administered intravenously 1 h after reperfusion. The results showed that anfibatide could significantly reduce infarct volumes, increase the number of intact neuronal cells and improve neurobehavioral function. Moreover, anfibatide could reduce post ischemic BBB damage by attenuating increased paracellular permeability in the ischemia hemisphere significantly. Stroke-induced increases in activity and protein expression of macrophage-1 antigen (MAC-1) and P-selectin were also reduced by anfibatide intervention. Finally, anfibatide exerted antithrombotic effects upon stroke by decreased the number of microthrombi formation. This is the first demonstration of anfibatide's efficacy in protecting the BBB integrity and decreasing neutrophil inflammation response mediated by MAC-1 besides microthrombus formation inhibition in the brain during reperfusion. Anfibatide, as a promising anti-thrombo-inflammation agent, could be beneficial for the treatment of ischemic stroke.