Background and Purpose Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147, also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Methods Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with anti-CD147 function blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24h after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. Results CD147 expression was rapidly increased in ischemic brain endothelium after tMCAO. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after tMCAO. The neuroprotective effects were associated with 1) prevented BBB damage, 2) decreased intravascular fibrin- and platelet- deposition, which in turn reduced thrombosis and increased cerebral perfusion, and 3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced nuclear factor NF-κB activation, matrix metalloproteinase-9 (MMP-9) activity, and plasminogen activator inhibitor-1 (PAI-1) expression in brain microvascular endothelial cells. Conclusions Inhibition of CD147 ameliorates acute ischemic stroke by reducing thrombo-inflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thrombo-inflammatory disorders.

Many neuroprotective agents, some promising, have been tested as adjunctive therapy with tPA to reduce its Background and Purpose-Taurine (2-aminoethansulfolic amino acid) exerts neuroprotective actions in experimental stroke. Here, we investigated the effect of taurine in combination with delayed tPA (tissue-type plasminogen activator) on embolic stroke. Methods-Rats subjected to embolic middle cerebral artery occlusion were treated with taurine (50 mg/kg) at 4 hours in combination with tPA (10 mg/kg) at 6 hours. Control groups consisted of ischemic rats treated with either taurine (50 mg/ kg) or saline at 4 hours or tPA (10 mg/kg) alone at 2 or 6 hours after middle cerebral artery occlusion. Results-We found that combination treatment with taurine and tPA robustly reduced infarct volume and neurological deficits 3 days after stroke, whereas treatment with taurine alone had a less-significant protective effect. tPA alone at 6 hours had no effects on infarct volume but instead induced intracerebral hemorrhage. The combination treatment with taurine prevented tPA-associated hemorrhage and reduced intravascular deposition of fibrin/fibrinogen and platelets in downstream microvessels and hence improved microvascular patency. These protective effects are associated with profound inhibition of CD147 (cluster of differentiation 147)-dependent MMP-9 (matrix metalloproteinase-9) pathway in ischemic brain endothelium by taurine. Notably, targeted inhibition of CD147 by intracerebroventricular injection of the rat CD147 siRNA profoundly inhibited ischemia-induced and tPA-enhanced MMP-9 activity in ischemic brain endothelium and blocked tPA-induced cerebral hemorrhage. Finally, the combination treatment with taurine and tPA improved long-term outcome at least 45 days after stroke compared with saline-treated group. Conclusions-Our results suggest that taurine in combination with tPA may be a clinically feasible approach toward future attempts at combination stroke therapy. Visual Overview-An online visual overview is available for this article.

Genetic and pharmacological inhibition of the phosphoinositide 3-kinase γ (PI3Kγ) exerts anti-inflammatory and protective effects in a number of inflammatory and autoimmune diseases. Spontaneously hypertensive rats subjected to embolic middle cerebral occlusion were treated with AS605240 (30 mg/kg) at 2 or 4 hours, tissue plasminogen activator (tPA, 10 mg/kg) at 2 or 6 hours, or AS605240 at 4 hours plus tPA at 6 hours. Infarct volume, brain hemorrhage, neurological function, microvascular thrombosis, and cerebral microvessel patency were examined. We found that treatment with AS605240 alone at 2 hours or the combination treatment with AS605240 at 4 hours and tPA at 6 hours significantly reduced infarct volume and neurological deficits at 3 days after stroke compared with ischemic rats treated with saline, AS605240 alone at 4 hours, and tPA alone at 6 hours. Moreover, the combination treatment effectively prevented the delayed tPA-induced cerebral hemorrhage. These protective effects are associated with reduced disruption of the blood brain barrier (BBB), reduced downstream microvascular thrombosis, and improved microvascular patency by AS605240. Inhibition of the nuclear transcription factor-kB (NF-kB)-dependent MMP-9 (matrix metalloproteinase-9) and PAI-1 (plasminogen activator inhibitor-1) in the ischemic brain endothelium may underlie the neurovascular protective effect of AS605240. In addition, the combination treatment significantly reduced circulating platelet P-selectin expression and platelet-leukocyte aggregation compared with ischemic rats treated with saline or tPA alone at 6 hours. In conclusion, inhibition of PI3Kγ with AS605240 reduces delayed tPA-induced intracerebral hemorrhage and improves microvascular patency, which likely contributes to neuroprotective effect of the combination treatment.

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