title: Hydrogen Sulfide Attenuates Tissue Plasminogen Activator-Induced Cerebral Hemorrhage Following Experimental Stroke.
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.
authors.affiliation: 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.|The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
authors.affiliation: 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. chengjian@suda.edu.cn.|The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. chengjian@suda.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
authors.affiliation: 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. jialijia8@sina.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D020520:Brain Infarction / Q000139:chemically induced / Q000188:drug therapy; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000188:drug therapy*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D005947:Glucose / Q000172:deficiency; D006862:Hydrogen Sulfide / Q000627:therapeutic use*; D000860:Hypoxia / Q000188:drug therapy; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012720:Severity of Illness Index; D020521:Stroke / Q000188:drug therapy; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
chemical_list: D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D005947:Glucose; D006862:Hydrogen Sulfide
keywords: Blood–brain barrier; Cerebral ischemia; Hemorrhage; Hydrogen sulfide; Tissue plasminogen activator