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Hydrogen Sulfide Attenuates Tissue Plasminogen Activator-Induced Cerebral Hemorrhage Following Experimental Stroke

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Abstract

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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Acknowledgments

This work received the financial support of grants from the National Science Foundation of China (81571124, 81471336, and 81371278) and from the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University (KF-GN-201203). Additionally, we appreciate the support from the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD) and the Jiangsu key laboratory grant (BM2013003).

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    Authors and Affiliations

    1. Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, 199 Renai Road, Suzhou, Jiangsu Province, 215123, China

      Hui Liu, Yi Wang, Yunqi Xiao & Jian Cheng

    2. The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

      Hui Liu, Zichun Hua & Jian Cheng

    3. Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou, Jiangsu Province, 215123, China

      Jia Jia

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    1. Hui Liu
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    Correspondence to Jian Cheng or Jia Jia.

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    J.J and J.C are the inventors of a patent on the therapeutic effects of ADT-derived hydrogen sulfide donors in stroke patients, which was approved by the China Intellectual Property Office.

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    Hui Liu and Yi Wang contributed equally to this work.

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    Liu, H., Wang, Y., Xiao, Y. et al. Hydrogen Sulfide Attenuates Tissue Plasminogen Activator-Induced Cerebral Hemorrhage Following Experimental Stroke. Transl. Stroke Res. 7, 209–219 (2016). https://doi.org/10.1007/s12975-016-0459-5

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