Understanding the Functions of Endogenous and Exogenous Tissue-Type Plasminogen Activator During Stroke

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. …