Early Abrogation of Gelatinase Activity Extends the Time Window for tPA Thrombolysis after Embolic Focal Cerebral Ischemia in Mice
2018
Abstract Acute ischemic stroke (AIS) is caused by clotting in the cerebral arteries, leading to brain oxygen deprivation and cerebral infarction. Recombinant human tissue plasminogen activator (tPA) is currently the only FDA-approved drug for ischemic stroke. However, tPA has to be administered within 4.5 h from the disease onset and delayed treatment of tPA can increase the risk of neurovascular impairment, including neuronal cell death, blood-brain barrier (BBB) disruption, and hemorrhagic transformation. A key contributing factor for tPA-induced neurovascular impairment is activation of matrix metalloproteinase-9 (MMP-9). We used a clinically-relevant mouse embolic model of focal-cerebral ischemia by insertion of a single embolus of blood clot to block the right middle cerebral artery. We showed that administration of the potent and highly selective gelatinase inhibitor SB-3CT extends the time window for administration of tPA, attenuating infarct volume, mitigating BBB disruption, and antagonizing the increase in cerebral hemorrhage induced by tPA treatment. We demonstrated that SB-3CT attenuates tPA-induced expression of vascular MMP-9, prevents gelatinase-mediated cleavage of extracellular laminin, rescues endothelial cells, and reduces caveolae-mediated transcytosis of endothelial cells. These results suggest that abrogation of MMP-9 activity mitigates the detrimental effects of tPA treatment, thus the combination treatment holds great promise for extending the therapeutic window for tPA thrombolysis, which opens the opportunity for clinical recourse to a greater number of patients. Significance Statement Endovascular thrombectomy benefited patients with disproportionately severe clinical deficit relative to infarct volume and provides a surgical option for treatment of ischemic stroke. Tissue-plasminogen activator (tPA) is the only FDA-approved clot-dissolving drug for treatment of ischemic stroke. However, its beneficial effect is seen only within 4.5 hours from the onset of stroke, with better outcomes observed the sooner treatment is given. Major risk is MMP-9−mediated neurovascular impairment. We document that early administration of the pharmacological agent SB 3 CT reduces MMP-9 levels and mitigates the side effects associated with tPA. Furthermore, it extends the time window for treatment with tPA after stroke holding great potential for both disease intervention and benefiting patients who might not otherwise be candidates for treatment with tPA.
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