Understanding the functions of endogenous and exogenous tissue-type plasminogen activator during stroke.

Fabian Docagne,Jérôme Parcq,Roger Lijnen,Denis Vivien,Carine Ali

doi:10.1161/strokeaha.114.006698

Abstract

Alteplase (Actilyse or Activase) is the gold standard acute treatment of ischemic stroke1 and receives attention for hematoma resolution in hemorrhagic stroke. The active principle of Alteplase is the recombinant form of an endogenous protease, tissue-type plasminogen activator (tPA). Its intravascular thrombolytic activity is well known, but less are its multifaceted functions in the central nervous system (CNS). Endogenous tPA is not only released in the blood by endothelial cells but also expressed by many cells within the brain parenchyma (online-only Data Supplement), and it can act on all cell types of the brain virtually. Endogenous tPA has been involved in an ever-increasing number of brain functions, of which several are highly relevant during and after stroke. Importantly, knowledge on the mechanisms of action of endogenous tPA may hold true for recombinant tPA. In this review, we provide an up-to-date overview of the current knowledge on the enzymatic or cytokine-like effects of action of tPA in the CNS, its various molecular substrates or receptors, focusing on the processes occurring during and after ischemic or hemorrhagic stroke, including excitotoxicity, apoptosis, blood–brain barrier breakdown, inflammation, axonal damage, and demyelination. tPA is a mosaic protease of 527 amino acids consisting of 5 distinct modules: a Finger domain, an epidermal growth factor (EGF)–like domain, 2 kringle domains (K1 and K2), and a serine protease proteolytic domain. Through these domains, tPA can interact with a variety of binding proteins and receptors in the brain parenchyma, thus extending its functions above the conversion of plasminogen into plasmin (Figure 1). Figure 1. Main cellular and molecular targets of tissue-type plasminogen activator in the central nervous system. BBB indicates blood–brain barrier, EGFR, epidermal growth factor receptor; LRP, low-density lipoprotein receptor–related protein; NMDAR, N-methyl-d-aspartate receptors; and PDGFR, platelet-derived growth factor receptor. tPA is not fibrinolytic by itself. …

Highlights

Alteplase (Actilyse or Activase) is the gold standard acute treatment of ischemic stroke[1] and receives attention for hematoma resolution in hemorrhagic stroke
We provide an up-to-date overview of the current knowledge on the enzymatic or cytokine-like effects of action of type plasminogen activator (tPA) in the central nervous system (CNS), its various molecular substrates or receptors, focusing on the processes occurring during and after ischemic or hemorrhagic stroke, including excitotoxicity, apoptosis, blood–brain barrier breakdown, inflammation, axonal damage, and demyelination
TPA Is More Than a Fibrinolytic Enzyme tPA is a mosaic protease of 527 amino acids consisting of 5 distinct modules: a Finger domain, an epidermal growth factor (EGF)–like domain, 2 kringle domains (K1 and K2), and a serine protease proteolytic domain

Summary

Basic Science Advances for Clinicians

Fabian Docagne, PhD; Jérôme Parcq, PhD; Roger Lijnen, PhD; Carine Ali, PhD; Denis Vivien, PhD. TPA Is More Than a Fibrinolytic Enzyme tPA is a mosaic protease of 527 amino acids consisting of 5 distinct modules: a Finger domain, an epidermal growth factor (EGF)–like domain, 2 kringle domains (K1 and K2), and a serine protease proteolytic domain Through these domains, tPA can interact with a variety of binding proteins and receptors in the brain parenchyma, extending its functions above the conversion of plasminogen into plasmin (Figure 1). Desmoteplase, the thrombolytic agent used in Desmoteplase in Acute Ischemic Stroke (DIAS) clinical trials, derived from a bat salivary gland, is closely related to tPA but lacks a K2 domain[18] and is devoid of toxic actions, likely because of the inability to interact with NMDARs.[19,20] the specific amino acids involved in the backbone structure of the lysine binding site are key in the ability of tPA to promote excitotoxicity on neurons.[21]. Some functions of tPA are specific to 1 form: for example, only the singlechain form of tPA can promote NMDAR-driven neurotoxicity.[22]

Role of tPA on the BBB Permeability

Effects of tPA on Apoptosis

Role of tPA in Axonal Damage and Regeneration

Findings

Conclusions and Prospects