中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (4): 620-624.doi: 10.4103/1673-5374.266904

• 综述:脑损伤修复保护与再生 • 上一篇    下一篇

尿激酶型纤溶酶原激活剂是中枢神经系统中突触可塑性的调节剂:对缺血性脑中神经修复的影响

  

  • 出版日期:2020-04-15 发布日期:2020-05-28

Urokinase-type plasminogen activator is a modulator of synaptic plasticity in the central nervous system: implications for neurorepair in the ischemic brain

Manuel Yepes1, 2, 3   

  1. 1 Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA, USA
    2 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
    3 Department of Neurology, Veterans Affairs Medical Center, Atlanta, GA, USA
  • Online:2020-04-15 Published:2020-05-28
  • Contact: Manuel Yepes, MD,myepes@emory.edu.
  • Supported by:
    This work was supported in part by National Institutes of Health Grant NS-091201 (to MY) and VA MERIT Award IO1BX003441 (to
    MY).

摘要: orcid: 0000-0002-5224-9663 (Manuel Yepes)

Abstract: The last two decades have witnessed a rapid decrease in mortality due to acute cerebral ischemia that paradoxically has led to a rapid increase in the number of patients that survive an acute ischemic stroke with various degrees of disability. Unfortunately, the lack of an effective therapeutic strategy to promote neurological recovery among stroke survivors has led to a rapidly growing population of disabled patients. Thus, understanding the mechanisms of neurorepair in the ischemic brain is a priority with wide scientific, social and economic implications. Cerebral ischemia has a harmful effect on synaptic structure associated with the development of functional impairment. In agreement with these observations, experimental evidence indicates that synaptic repair underlies the recovery of neurological function following an ischemic stroke. Furthermore, it has become evident that synaptic plasticity is crucial not only during development and learning, but also for synaptic repair after an ischemic insult. The plasminogen activating system is assembled by a cascade of enzymes and their inhibitors initially thought to be solely involved in the generation of plasmin. However, recent work has shown that in the brain this system has an important function regulating the development of synaptic plasticity via mechanisms that not always require plasmin generation. Urokinase-type plasminogen activator (uPA) is a serine proteinase and one of the plasminogen activators, that upon binding to its receptor (uPAR) not only catalyzes the conversion of plasminogen into plasmin on the cell surface, but also activates cell signaling pathways that promote cell migration, proliferation and survival. The role of uPA is the brain is not fully understood. However, it has been reported while uPA and uPAR are abundantly found in the developing central nervous system, in the mature brain their expression is restricted to a limited group of cells. Remarkably, following an ischemic injury to the mature brain the expression of uPA and uPAR increases to levels comparable to those observed during development. More specifically, neurons release uPA during the recovery phase from an ischemic injury, and astrocytes, axonal boutons and dendritic spines recruit uPAR to their plasma membrane. Here we will review recent evidence indicating that binding of uPA to uPAR promotes the repair of synapses damaged by an ischemic injury, with the resultant recovery of neurological function. Furthermore, we will discuss data indicating that treatment with recombinant uPA is a potential therapeutic strategy to promote neurological recovery among ischemic stroke survivors.

Key words: cerebral ischemia, neurorepair, plasminogen, plasticity, stoke, synapse, urokinase, urokinase receptor