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

  • Jiayi Zhu
  • Yan Wan
  • Hexiang Xu
  • Yulang Wu
  • Bo HuEmail author
  • Huijuan JinEmail author


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.


Endogenous tPA Ischemic stroke Neuronal survival Pleiotropic functions Signal 



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).

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Neurology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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