Abstract
BackgroundA recent study suggests that patients with persistent occlusion of the middle cerebral artery (MCA) following treatment with recombinant tissue plasminogen activator (rt-PA) have better outcomes than patients with MCA occlusion not receiving rt-PA. We performed a study to elucidate possible mechanisms of this finding in a new model of thromboembolic stroke closely mimicking human pathophysiology.MethodsThromboembolic stroke was induced by local injection of thrombin directly into the right MCA of C57 black/6J mice. Rt-PA was administered 20 and 40 min after clot formation. The efficiency of rt-PA to induce thrombolysis was measured by laser Doppler. After 24 h, all animals were euthanized and interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP)-9, Caspase-3, hsp 32 and hsp 70 protein levels were investigated by immunofluorescence. Presence of hemorrhage was verified and infarct volume was measured using histology.ResultsThrombin injection resulted in clot formation giving rise to cortical brain infarction. Early rt-PA treatment starting at 20 min after the clot formation resulted in 100% recanalization. However, rt-PA-induced thrombolysis dissolved the clot in only 38% of the animals when administered 40 min after clot formation. Protein levels of IL-6, TNF-α, MMP-9, Caspase-3, hsp 32 and hsp 70 were increased after MCAO, whereas treatment with rt-PA attenuated the expressions of inflammatory markers in those animals where the thrombolysis was successful. In addition, the infarct size was significantly reduced with rt-PA treatment compared to non-treated MCAO, regardless of whether MCA thrombolysis was successful.ConclusionsThe present study demonstrates a clear correlation of the protein expression of inflammatory mediators, apoptosis and stress genes with the recanalization data after rt-PA treatment. In this model rt-PA treatment decreases the infarct size regardless of whether vessel recanalization is successful.
Highlights
Sudden occlusion of a cerebral blood vessel by a thrombus or embolism initiates a complex process of events that includes excitotoxity, oxidative stress, microvascular injury, blood brain barrier dysfunction and postischemic inflammation that leads to cell death
Thromboembolic Stroke Model Thrombin injection resulted in stable clot formation and cortical brain injury in 62% of the animals
Effects of the recombinant tissue plasminogen activator (rt-PA) on CBF There is a significant variability in the response to rt-PA at different time-points after clot formation
Summary
Sudden occlusion of a cerebral blood vessel by a thrombus or embolism initiates a complex process of events that includes excitotoxity, oxidative stress, microvascular injury, blood brain barrier dysfunction and postischemic inflammation that leads to cell death. Several mechanisms are involved in the pathophysiology of stroke, increasing evidence shows that inflammation is a key contributor to the pathophysiology of cerebrovascular diseases [1,2,3] and this correlates with the outcome of the patient. The only approved therapy for acute thromboembolic stroke remains thrombolysis with recombinant tissue plasminogen activator (rt-PA) within the first 4,5 hours after symptom onset [8,9,10]. This study aims to elucidate possible mechanisms of this finding in a new model of thromboembolic stroke closely mimicking human pathophysiology. A recent study suggests that patients with persistent occlusion of the middle cerebral artery (MCA) following treatment with recombinant tissue plasminogen activator (rt-PA) have better outcomes than patients with MCA occlusion not receiving rt-PA. We performed a study to elucidate possible mechanisms of this finding in a new model of thromboembolic stroke closely mimicking human pathophysiology
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