期刊
BIOMED RESEARCH INTERNATIONAL
卷 2018, 期 -, 页码 -出版社
HINDAWI LTD
DOI: 10.1155/2018/8943210
关键词
-
资金
- National Science and Technology Major Projects for Major New Drugs Innovation and Development [2013ZX09508104, 2013ZX09402203]
- National Natural Science Foundation of China [81102444, 81771293]
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2016-I2M-3-007, 2017-I2M-010]
- Central Public Scientific Research Institution Fundamental Project [2014CX05]
- National Key Research and Development Program of China [2016YFC1000905]
- Shenzhen Basic Research Program [JCYJ20170413165705083, JCYJ20170307170338498]
Tissue-type plasminogen activator (t-PA) remains the only approved therapy for acute ischemic stroke but has a restrictive treatment time window of 4.5 hr. Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of hemorrhagic transformation (HT) secondary to reperfusion. In this study, we sought to determine the effect of pinocembrin (PCB; a pleiotropic neuroprotective agent) on t-PA administration-induced BBB damage in a novel rat thromboembolic stroke model. By assessing the leakage of Evans blue into the ischemic hemisphere, we demonstrated that PCB pretreatment 5 min before t-PA administration significantly reduced BBB damage following 2 hr, 4 hr, 6 hr, and even 8 hr ischemia. Consistently, PCB pretreatment significantly decreased t-PAinfusion-resulting brain edema and infarction volume and improved the behavioral outcomes following 6 hr ischemia. Mechanistically, PCB pretreatment inhibited the activation of MMP-2 and MMP-9 and degradation of tight junction proteins (TJPs) occludin and claudin-5 in the ischemic hemisphere. Moreover, PCB pretreatment significantly reduced phosphorylation of platelet-derived growth factor receptor alpha (PDGFR alpha) as compared with t-PA alone. In an in vitro BBB model, PCB decreased transendothelial permeability upon hypoxia/aglycemia through inhibiting PDGF-CC secretion. In conclusion, we demonstrated that PCB pretreatment shortly before t-PA infusion significantly protects BBB function and improves neurological outcomes following prolonged ischemia beyond the regular 4.5 hr t-PA time window. PCB pretreatment may represent a novel means of increasing the safety and the therapeutic time window of t-PA following ischemic stroke.
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