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Early Abrogation of Gelatinase Activity Extends the Time Window for tPA Thrombolysis after Embolic Focal Cerebral Ischemia in Mice.
- Source :
-
ENeuro [eNeuro] 2018 Jun 27; Vol. 5 (3). Date of Electronic Publication: 2018 Jun 27 (Print Publication: 2018). - Publication Year :
- 2018
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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 Food and Drug Administration-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.
- Subjects :
- Animals
Blood-Brain Barrier metabolism
Brain Ischemia prevention & control
Caveolin 1 metabolism
Disease Models, Animal
Endothelial Cells drug effects
Endothelial Cells metabolism
Gelatinases antagonists & inhibitors
Heterocyclic Compounds, 1-Ring administration & dosage
Laminin metabolism
Male
Matrix Metalloproteinase 9 metabolism
Matrix Metalloproteinase Inhibitors administration & dosage
Mice, Inbred C57BL
Sulfones administration & dosage
Brain Ischemia enzymology
Gelatinases metabolism
Tissue Plasminogen Activator administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2373-2822
- Volume :
- 5
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- ENeuro
- Publication Type :
- Academic Journal
- Accession number :
- 29963617
- Full Text :
- https://doi.org/10.1523/ENEURO.0391-17.2018