Hydrogen Sulfide Attenuates Tissue Plasminogen Activator-Induced Cerebral Hemorrhage Following Experimental Stroke
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ORIGINAL ARTICLE
Hydrogen Sulfide Attenuates Tissue Plasminogen Activator-Induced Cerebral Hemorrhage Following Experimental Stroke Hui Liu 1,2 & Yi Wang 1 & Yunqi Xiao 1 & Zichun Hua 2 & Jian Cheng 1,2 & Jia Jia 3
Received: 24 November 2015 / Revised: 3 February 2016 / Accepted: 9 March 2016 # Springer Science+Business Media New York 2016
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
Hui Liu and Yi Wang contributed equally to this work. * Jian Cheng [email protected] * Jia Jia [email protected]
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
2
The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
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
attenuated by ADT-OH. In the in vitro glucose–oxygen deprivation (OGD) model, ADT-OH markedly attenuated tPAenhanced 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-VEGFMMP9 cascade. Administration of H2S donors has potential as a novel modality to improve the safety of tPA following stroke. Keywords Cerebral ischemia . Hydrogen sulfide . Tissue plasminogen activator . Hemorrhage . Blood–brain barrier
Introduction Stroke is the leading cause of death and disability worldwide. Fibrinolytic therapy with recombinant tissue plasminogen activator (tPA) is the only globally accepted treatment for ischemic stroke [1]. Unfortunately, the clinical application of tPA remains rather limited due to the enhanced risk of cerebral hemorrhage associated with tPA therapy [2]. Hemorrhagic transformation is the most important obstacle for the clinical use of tPA in patients with ischemic stroke [3
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