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  • Title: Hydrogen Sulfide Attenuates Tissue Plasminogen Activator-Induced Cerebral Hemorrhage Following Experimental Stroke.
    Author: Liu H, Wang Y, Xiao Y, Hua Z, Cheng J, Jia J.
    Journal: Transl Stroke Res; 2016 Jun; 7(3):209-19. PubMed ID: 27018013.
    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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