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The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?

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Abstract

Endogenous protease tissue-type plasminogen activator (tPA) has highly efficient fibrinolytic activity and its recombinant variants alteplase and tenecteplase are established as highly effective thrombolytic drugs for ischemic stroke. Endogenous tPA is constituted of five functional domains through which it interacts with a variety of substrates, binding proteins and receptors, thus having enzymatic and cytokine-like effects to act on all cell types of the brain. In the past 2 decades, numerous studies have explored the clinical relevance of endogenous tPA in neurological diseases, especially in ischemic stroke. tPA is released from many cells within the brain parenchyma exposed to ischemia conditions in vitro and in vivo, which is believed to control neuronal fate. Some studies proved that tPA could induce blood–brain barrier disruption, neural excitotoxicity and inflammation, while others indicated that tPA also has anti-excitotoxic, neurotrophic and anti-apoptotic effects on neurons. Therefore, more work is needed to elucidate how tPA mediates such opposing functions that may amplify tPA from a therapeutic means into a key therapeutic target in endogenous neuroprotection after stroke. In this review, we summarize the biological characteristics and pleiotropic functions of tPA in the brain. Then we focus on possible hypotheses about why and how endogenous tPA mediates ischemic neuronal death and survival. Finally, we analyze how endogenous tPA affects neuron fate in ischemic stroke in a comprehensive view.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2018YFC1312200 to Bo Hu) and National Natural Science Foundation of China (Grants: 81571119 and 81371311 to BH, and 81671147 to JHJ).

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  1. Jiayi Zhu and Yan Wan contributed equally to this work.

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  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China

    Jiayi Zhu, Yan Wan, Hexiang Xu, Yulang Wu, Bo Hu & Huijuan Jin

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  1. Jiayi Zhu
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  2. Yan Wan
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Zhu, J., Wan, Y., Xu, H. et al. The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?. Cell. Mol. Life Sci. 76, 1489–1506 (2019). https://doi.org/10.1007/s00018-019-03005-8

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