Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke

Abstract

Ischemic stroke continues to be one of the most challenging diseases in translational neurology. Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited to the first hours after stroke onset due to an increased risk of hemorrhagic transformation over time resulting in enhanced brain injury. In this review we discuss the role of matrix metalloproteinases (MMPs) in blood-brain barrier (BBB) disruption as a consequence of ischemic stroke. MMP-9 in particular appears to play an important role in tPA-associated hemorrhagic complications. Reactive oxygen species can enhance the effects of tPA on MMP activation through the loss of caveolin-1 (cav-1), a protein encoded in the cav-1 gene that serves as a critical determinant of BBB permeability. This review provides an overview of MMPs' role in BBB breakdown during acute ischemic stroke. The possible role of MMPs in combination treatment of acute ischemic stroke is also examined.

Keywords: blood-brain barrier; caveolin-1; matrix metalloproteinases; reactive oxygen species; stroke.

Figure 1

Mechanisms in MMP activation leading to degradation of extracellular matrix and blood-brain barrier disruption/hemorrhage. Acute stroke may lead to vascular endothelial cell injury causing the release of proinflammatory cytokines and free radicals at the neurovascular unit activating MMPs. tPA administration may likewise induce MMPs through the LRP, PAR1, and PDGRF-α pathways. MMP activation is inhibited by several agents including imatinib, activation protein C (APC), cilostazol, melatonin, BB-94, GM6001, fasudil, AHA, NYX-059, and edaravone (Table 2). LRP, lipoprotein receptor-related protein; MMP, matrix metalloproteinase; PAR1, protease-activated receptor 1; tPA, tissue type plasminogen activator. Figure modified from Yamashita and Abe (2011).