Delivery of anti-platelet-endothelial cell adhesion molecule single-chain variable fragment-urokinase fusion protein to the cerebral vasculature lyses arterial clots and attenuates postischemic brain edema. Academic Article uri icon

Overview

MeSH

  • Animals
  • Blood-Brain Barrier
  • Brain
  • Brain Chemistry
  • Cerebellum
  • Cerebrovascular Circulation
  • Fibrinolysis
  • Injections, Intra-Arterial
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prodrugs
  • Recombinant Fusion Proteins
  • Temporal Lobe
  • Thrombolytic Therapy

MeSH Major

  • Antigens, CD31
  • Brain Edema
  • Drug Delivery Systems
  • Immunoglobulin Fragments
  • Intracranial Thrombosis
  • Urokinase-Type Plasminogen Activator

abstract

  • Efficacy and safety of current means to prevent cerebrovascular thrombosis in patients at high risk of stroke are suboptimal. In theory, anchoring fibrinolytic plasminogen activators to the luminal surface of the cerebral endothelium might arrest formation of occlusive clots in this setting. We tested this approach using the recombinant construct antiplatelet-endothelial cell adhesion molecule (PECAM) single-chain variable fragment (scFv)-urokinase-type plasminogen activator (uPA), fusing low-molecular-weight single-chain urokinase-type plasminogen activator with a scFv of an antibody directed to the stably expressed endothelial surface determinant PECAM-1, implicated in inflammation and thrombosis. Studies in mice showed that scFv-uPA, but not unconjugated uPA 1) accumulates in the brain after intravascular injection, 2) lyses clots lodged in the cerebral arterial vasculature without hemorrhagic complications, 3) provides rapid and stable cerebral reperfusion, and 4) alleviates post-thrombotic brain edema. Effective and safe thromboprophylaxis in the cerebral arterial circulation by anti-PECAM scFv-uPA represents a prototype of a new paradigm to prevent recurrent cerebrovascular thrombosis.

publication date

  • June 2007

has subject area

  • Animals
  • Antigens, CD31
  • Blood-Brain Barrier
  • Brain
  • Brain Chemistry
  • Brain Edema
  • Cerebellum
  • Cerebrovascular Circulation
  • Drug Delivery Systems
  • Fibrinolysis
  • Immunoglobulin Fragments
  • Injections, Intra-Arterial
  • Intracranial Thrombosis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prodrugs
  • Recombinant Fusion Proteins
  • Temporal Lobe
  • Thrombolytic Therapy
  • Urokinase-Type Plasminogen Activator

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1124/jpet.107.120535

PubMed ID

  • 17389242

Additional Document Info

start page

  • 947

end page

  • 952

volume

  • 321

number

  • 3