Early Abrogation of Gelatinase Activity Extends the Time Window for tPA Thrombolysis after Embolic Focal Cerebral Ischemia in Mice.
Shanyan ChenZhenzhou ChenJiankun CuiMyah L McCraryHailong SongShahriar MobasheryMayland ChangZezong GuPublished in: eNeuro (2018)
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.
Keyphrases
- blood brain barrier
- cerebral ischemia
- subarachnoid hemorrhage
- acute ischemic stroke
- endothelial cells
- cell death
- brain injury
- high glucose
- end stage renal disease
- magnetic resonance imaging
- middle cerebral artery
- heart failure
- drug administration
- poor prognosis
- emergency department
- recombinant human
- mouse model
- type diabetes
- newly diagnosed
- chronic kidney disease
- deep learning
- acute coronary syndrome
- atrial fibrillation
- ejection fraction
- internal carotid artery
- signaling pathway
- smoking cessation
- coronary artery disease
- long non coding rna
- patient reported
- pet ct
- patient reported outcomes
- image quality
- skeletal muscle
- machine learning
- percutaneous coronary intervention
- electronic health record
- climate change