Review
Molecular insights and therapeutic targets for blood–brain barrier disruption in ischemic stroke: Critical role of matrix metalloproteinases and tissue-type plasminogen activator

https://doi.org/10.1016/j.nbd.2010.03.008Get rights and content

Abstract

Blood–brain barrier (BBB) disruption, mediated through matrix metalloproteinases (MMPs) and other mechanisms, is a critical event during ischemic stroke. Tissue plasminogen activator (tPA) is the only FDA-approved thrombolytic therapy for acute ischemic stroke, but the efficacy and safety of its therapeutic application are limited by narrow treatment time windows and side effects. Thus, there is a pressing need to develop combinational therapy that could offset tPA side effects and improve efficacy in clinical practice. Recent experimental studies indicate that tPA has previously unidentified functions in the brain beyond its well-established thrombolytic activity, which might contribute to tPA-related side effects through MMPs (mainly MMP-9) and several signaling pathways involved in LDL receptor-related protein (LRP), activated protein C (APC) and protease-activated receptor 1 (PAR-1), platelet-derived growth factor C (PDGF-C), and N-methyl-d-aspartate (NMDA) receptor. Therapeutic targeting of MMPs and/or tPA-related signaling pathways might offer promising new approaches to combination therapies for ischemic stroke. This review provides an overview of the relationship between structural components and function of the BBB/neurovascular unit with respect to ischemic stroke. We discuss how MMPs and tPA contribute to BBB disruption during ischemic stroke and highlight recent findings of molecular signaling pathways involved in neurotoxicity of tPA therapy.

Introduction

The blood–brain barrier (BBB) is primarily formed by specialized brain endothelial cells that are interconnected by well-developed tight junctions and provides a dynamic interface between the blood and the brain (Abbott et al., 2010). BBB disruption is a critical event in the pathogenesis of acute ischemic stroke; however, the molecular mechanisms involved are not completely understood (Sandoval and Witt, 2008). Emerging studies indicate that matrix metalloproteinases (MMPs) and tissue-type plasminogen activator (tPA) play critical roles in the BBB disruption during acute ischemic stroke (Adibhatla and Hatcher, 2008). Experimental data suggest that MMPs have deleterious roles in the early phase of ischemic stroke, but also have beneficial roles in stroke recovery during the later phase. By degrading neurovascular matrix and disruption of the BBB tight junctions, MMPs (mainly MMP-9) promote BBB damage, brain edema, and hemorrhage during acute ischemic stroke (Sandoval and Witt, 2008). tPA is the only thrombolytic drug approved by the US FDA, but the efficacy and safety of its therapeutic application are limited by narrow treatment time windows (within 3 hours of the onset of stroke symptoms) and side effects on brain edema and hemorrhagic complications (Cronin, 2010, Derex & Nighoghossian, 2008, Gravanis & Tsirka, 2008). Experimental data have shown that tPA has pleiotropic actions in the brain beyond its well-established thrombolytic role, including activation of MMPs and other molecular pathways (Adibhatla & Hatcher, 2008, Yepes et al., 2009, Rosell & Lo, 2008). These effects may increase tPA neurotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage (Adibhatla & Hatcher, 2008, Yepes et al., 2009). Thus, combination therapies targeting MMPs and other tPA-related pathways may limit neurotoxic effects and extend treatment time windows of tPA in ischemic stroke. This review provides an overview of the relationship between structural components and function of the BBB with respect to ischemic stroke. We discuss how MMPs and tPA contribute to BBB disruption during ischemic stroke and highlight recent findings of molecular signaling pathways involved in neurotoxicity of tPA therapy.

Section snippets

The blood–brain barrier structural component and functional integrity

The structure and function of the bloodbrain barrier (BBB) has been discussed in reviews elsewhere (Sandoval & Witt, 2008, Abbott et al., 2010). Structural and molecular components of the BBB are summarized in Fig. 1. Briefly, the BBB comprises the tight junctions (TJs) and adherens junctions (AJs). TJs are continuous membrane strands located at the apical site between brain endothelial cells (ECs), which consist of three integral protein types: claudins, occludin, and junctional adhesion

Expression, activation, and function of MMPs in BBB disruption in ischemic stroke

Matrix metalloproteinases (MMPs) comprise a family of zinc endopeptidases that can broadly target almost all components of the mammalian central nervous system (CNS). Emerging evidence indicates that MMPs play both detrimental and beneficial roles in ischemic stroke. In the early phase (hours to days) after cerebral ischemia, MMPs disrupt the BBB by degrading the TJ proteins (e.g., occludin and claudin-5) and basal lamina proteins (e.g., fibronectin, laminin, collagen, proteoglycans, and

Expression and neurotoxicity of tPA in BBB disruption during ischemic stroke

Thrombolytic therapy with tissue-type plasminogen activator (tPA) for ischemic stroke represents a two-edged sword, since tPA promotes desirable (thrombolytic) as well as undesirable (neurotoxic) outcomes during stroke (Adibhatla and Hatcher, 2008). It has been established that exogenous tPA can cross both the intact and the damaged BBB to reach the brain parenchyma (Adibhatla & Hatcher, 2008, Yepes et al., 2009). Thus, both endo- and exogenous tPAs are capable of influencing brain functions

Concluding remarks

Cerebral I/R injury induces dynamic changes in the BBB permeability, but the underlying mechanisms have remained largely unknown. More efforts are needed to better understand the molecular mechanism underlying the degradation and redistribution of various protein components of the BBB according to the type, severity, and duration of cerebral ischemic insults. Since clinical trials indicate that a singular focus on saving neurons alone does not work for stroke, in recent years, the concept of

Acknowledgments

The work was supported by the National Institutes of Health grant HL087990 (Dr Li) and by a scientist development grant (0530166N, Dr Li) from the American Heart Association. We gratefully thank our colleagues for many helpful discussions.

Authorship

The concept and design and writing of the manuscript (Dr. Li).

The literature search and discussion of the manuscript (Drs. Jin and Yang, equally contributed to this work).

References (141)

  • A.S. Fanning

    The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton

    J. Biol. Chem.

    (1998)
  • C. Feistritzer et al.

    Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation

    Blood

    (2005)
  • G.J. Feldman

    Occludin: structure, function and regulation

    Adv. Drug Deliv. Rev.

    (2005)
  • L. Fredriksson

    Structural requirements for activation of latent platelet-derived growth factor CC by tissue plasminogen activator

    J. Biol. Chem.

    (2005)
  • H. Guo

    Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3

    Neuron

    (2004)
  • K.J. Gurney

    Bloodbrain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation

    Neurobiol. Dis.

    (2006)
  • K. Jian Liu et al.

    Matrix metalloproteinases and free radicals in cerebral ischemia

    Free Radic. Biol. Med.

    (2005)
  • T. Kago

    Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries

    Biochem. Biophys. Res. Commun.

    (2006)
  • G. Kale

    Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3

    Biochem. Biophys. Res. Commun.

    (2003)
  • C.H. Lai

    Critical role of actin in modulating BBB permeability

    Brain Res. Brain Res. Rev.

    (2005)
  • N. Lebeurrier

    The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo

    Mol. Cell. Neurosci.

    (2005)
  • T. Nassar

    Binding of urokinase to low density lipoprotein-related receptor (LRP) regulates vascular smooth muscle cell contraction

    J. Biol. Chem.

    (2002)
  • A.M. Planas

    Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia

    Neurobiol. Dis.

    (2001)
  • R. Polavarapu

    Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit

    Blood

    (2007)
  • A. Rosell et al.

    Multiphasic roles for matrix metalloproteinases after stroke

    Curr. Opin. Pharmacol.

    (2008)
  • R.M. Adibhatla et al.

    Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies

    CNS Neurol. Disord. Drug Targets

    (2008)
  • I.E. András

    The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells

    J. Cereb. Blood Flow Metab.

    (2007)
  • D.C. Anthony

    Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke

    Neuropathol. Appl. Neurobiol.

    (1997)
  • M. Asahi

    Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94

    J. Cereb. Blood Flow Metab.

    (2000)
  • M. Asahi

    Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia

    NeuroReport

    (2001)
  • M. Asahi

    Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia

    J. Neurosci.

    (2001)
  • M.S. Balda

    Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein

    J. Cell. Biol.

    (1996)
  • T.L. Barr

    Bloodbrain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9

    Stroke

    (2010)
  • A.T. Bauer

    Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement

    Cereb. Blood Flow Metab.

    (2009)
  • K. Benchenane

    Tissue-type plasminogen activator crosses the intact bloodbrain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis

    Circulation

    (2005)
  • K. Benchenane

    Oxygen glucose deprivation switches the transport of tPA across the bloodbrain barrier from an LRP-dependent to an increased + LRP-independent process

    Stroke

    (2005)
  • K. Benchenane

    Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory

    J. Cell Sci.

    (2007)
  • G.R. Bernard

    Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis

    N. Engl. J. Med.

    (2001)
  • B.H. Buck

    Early neutrophilia is associated with volume of ischemic tissue in acute stroke

    Stroke

    (2008)
  • M. Castellanos

    Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke

    Stroke

    (2003)
  • M. Castellanos

    Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study

    Stroke

    (2007)
  • D. Centonze

    Tissue plasminogen activator is required for corticostriatal long-term potentiation

    Eur. J. NeuroSci.

    (2002)
  • M.R. Cera

    JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling

    J. Cell Sci.

    (2009)
  • D.I. Chang

    Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia

    J. Cereb. Blood Flow Metab.

    (2003)
  • B. Chen

    Severe bloodbrain barrier disruption and surrounding tissue injury

    Stroke

    (2009)
  • F. Chen

    Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure

    Hepatology

    (2009)
  • T. Cheng

    Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective

    Nat. Med.

    (2003)
  • T. Cheng

    Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage

    Nat. Med.

    (2006)
  • L.A. Cunningham

    Multiple roles for MMPs and TIMPs in cerebral ischemia

    Glia

    (2005)
  • G.J. Del Zoppo

    Stroke and neurovascular protection

    N. Engl. J. Med.

    (2006)
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