Journal
TRANSLATIONAL STROKE RESEARCH
Volume 7, Issue 3, Pages 209-219Publisher
SPRINGER
DOI: 10.1007/s12975-016-0459-5
Keywords
Cerebral ischemia; Hydrogen sulfide; Tissue plasminogen activator; Hemorrhage; Blood-brain barrier
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Funding
- National Science Foundation of China [81571124, 81471336, 81371278]
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University [KF-GN-201203]
- Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)
- Jiangsu key laboratory grant [BM2013003]
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Tissue plasminogen activator (tPA), the only approved drug for the treatment of ischemic stroke, increases the risk of cerebral hemorrhage. Here, we investigated whether the newly identified gaso-transmitter hydrogen sulfide (H2S), when used in combination with tPA, reduced the hemorrhagic transformation following stroke. In a mouse model of middle cerebral artery occlusion (MCAO), intravenous injection of tPA enhanced cerebral hemorrhage, which was significantly attenuated by the co-administration of two structurally unrelated H2S donors, ADT-OH and NaHS. By assessing extravasation of Evans blue into the ischemic hemisphere as well as brain edema following MCAO, we further showed that a tPA-exacerbated BBB disruption was significantly ameliorated by the co-administration of ADT-OH. In the mouse MCAO model, tPA upregulated Akt activation, vascular endothelial growth factor (VEGF) expression, and metalloproteinase 9 (MMP9) activity in the ischemic brain, which was remarkably attenuated by ADT-OH. In the in vitro glucose-oxygen deprivation (OGD) model, ADT-OH markedly attenuated tPA-enhanced Akt activation and VEGF expression in brain microvascular endothelial cells. Finally, ADT-OH improved functional outcomes in mice subjected to MCAO and tPA infusion. In conclusion, H2S donors reduced tPA-induced cerebral hemorrhage by possibly inhibiting the Akt-VEGF-MMP9 cascade. Administration of H2S donors has potential as a novel modality to improve the safety of tPA following stroke.
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