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Review
. 2010 Jun;38(3):376-85.
doi: 10.1016/j.nbd.2010.03.008. Epub 2010 Mar 17.

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

Rong Jin  1 , Guojun Yang, Guohong Li
Affiliations
Review

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

Rong Jin et al. Neurobiol Dis. 2010 Jun.

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.

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Figures

Figure 1
Figure 1
Schematic diagram of the BBB structure that comprises the tight and adherens junctions. The tight junctions consist of occludin, claudins, and junctional adhesion molecules (JAM). The tight junctions also consist of several accessory proteins necessary to form structural support, including the zonula occluden (ZO) proteins, AF6, 7H6, cingulin, and others. Most of the tight junction components (ZO proteins, claudin, and occludin) have the ability to bind to actin cytoskeleton in brain endothelial cells. The adherens junctions consist of vascular endothelial cadherin (VE-cadherin) and catenin proteins and provide structural integrity and attachment between the cells, and are necessary for formation of tight junctions. Updated from Abbott NJ, 2009 and other sources.
Figure 2
Figure 2
Mechanisms of activation of MMPs. ProMMP-2 can be activated by membrane-type-1 MMP (MT1-MMP/MMP-14), and the latter can be activated by furin. ProMMP-9 can be activated by MMP-3, tissue type plasminogen activator (tPA), proinflammatory factors (e.g. IL-1β and TNF-α) and reactive oxygen species (ROS). Plasmin can activate both MT1-MMP and MMP-3. tPA can activate both MMP-3 and MMP-9 through multiple pathways. tPA activity can be inhibited by neuroserpin and activated protein C (APC).
Figure 3
Figure 3
Schematic diagram of the neurovascular unit that comprises neurons, microvessels (endothelium), astrocytes, and pericytes that reside within the basement membrane. Neurons and microvessels communicate through astrocytes (updated from del Zoppo GJ, 2006 and other sources). There is spatiotemporal change of MMP-9 expression within the neurovascular unit after ischemic stroke. In the acute phase (within 24h), MMP-9 is mainly derived from brain endothelial cells and infiltrating leukocytes (especially neutrophils). In the late phase, MMP-9 is mainly secreted by astrocytes and neurons. Updated from Zlokovic BV, 2006 and other sources.
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