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Mechanisms in blood-brain barrier opening and metabolism-challenged cerebrovascular ischemia with emphasis on ischemic stroke

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Abstract

Stroke is the leading cause of disability among adults as well as the 2nd leading cause of death globally. Ischemic stroke accounts for about 85% of strokes, and currently, tissue plasminogen activator (tPA), whose therapeutic window is limited to up to 4.5 h for the appropriate population, is the only FDA approved drug in practice and medicine. After a stroke, a cascade of pathophysiological events results in the opening of the blood-brain barrier (BBB) through which further complications, disabilities, and mortality are likely to threaten the patient’s health. Strikingly, tPA administration in eligible patients might cause hemorrhagic transformation and sustained damage to BBB integrity. One must, therefore, delineate upon stroke onset which cellular and molecular factors mediate BBB permeability as well as what key roles BBB rupture plays in the pathophysiology of stroke. In this review article, given our past findings of mechanisms underlying BBB opening in stroke animal models, we elucidate cellular, subcellular, and molecular factors involved in BBB permeability after ischemic stroke. The contribution of each factor to stroke severity and outcome is further discussed. Determinant factors in BBB permeability and stroke include mitochondria, miRNAs, matrix metalloproteinases (MMPs), immune cells, cytokines, chemokines, and adhesion proteins. Once these factors are interrogated and their roles in the pathophysiology of stroke are determined, novel targets for drug discovery and development can be uncovered in addition to novel therapeutic avenues for human stroke management.

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Funding

The work was supported by AHA (16SDG31170008 to XR), NSF (1008182R to XR), WVCTSI (NIH/NIGMS U54GM104942 to XR), WVU Bridge Funding Grant (to XR) and NIH (P20 GM109098 to JWS).

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  1. Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA

    Sajad Sarvari, Emily Hone, James W. Simpkins & Xuefang Ren

  2. Department of Biochemistry, West Virginia University, Morgantown, WV, USA

    Faezeh Moakedi

  3. Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, USA

    Emily Hone & Xuefang Ren

  4. Experimental Stroke Core Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA

    James W. Simpkins & Xuefang Ren

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  1. Sajad Sarvari
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Sarvari, S., Moakedi, F., Hone, E. et al. Mechanisms in blood-brain barrier opening and metabolism-challenged cerebrovascular ischemia with emphasis on ischemic stroke. Metab Brain Dis 35, 851–868 (2020). https://doi.org/10.1007/s11011-020-00573-8

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