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