Glutamate-Mediated Blood–Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery

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Abstract

The blood–brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood–brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood–brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo. Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood–brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood–brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders.

SIGNIFICANCE STATEMENT In this study, we reveal a new mechanism that governs blood–brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.

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Author and article information

Journal

Journal ID (nlm-ta): J Neurosci

Journal ID (iso-abbrev): J. Neurosci

Journal ID (hwp): jneuro

Journal ID (pmc): jneurosci

Journal ID (publisher-id): J. Neurosci

Title: The Journal of Neuroscience

Publisher: Society for Neuroscience

ISSN (Print): 0270-6474

ISSN (Electronic): 1529-2401

Publication date (Print): 20 July 2016

Publication date PMC-release: 20 January 2017

Volume: 36

Issue: 29

Pages: 7727-7739

Affiliations

[1] ¹Departments of Cognitive and Brain Sciences,

[2] ²Physiology and Cell Biology,

[3] ³Biomedical Engineering, and

[4] ⁴Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, 84105 Israel,

[5] ⁵Brainsway, Jerusalem, 9777518 Israel,

[6] ⁶Atid, Rome 00187, Italy,

[7] ⁷Departments of Neurology and Psychiatry and

[8] ⁸Neurological Sciences, Sapienza University of Rome, Rome 00185, Italy, and

[9] ⁹Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada

Author notes

Correspondence should be addressed to Alon Friedman, 5850 College Street, P.O. Box 15000, Halifax, Nova Scotia B3H 4R2, Canada. alon.friedman@ 123456dal.ca

Author contributions: U.V., R.V., G.S.P., A.Z., M.I., and A.F. designed research; U.V., R.V., G.S.P., O.P., M.F., Y.C., Y.R., H.S., R.R., E.O., M.C., C.C., A.S., M.S., A.D., V.N., and A.F. performed research; U.V., R.V., O.P., M.F., Y.C., Y.R., H.S., A.Z., R.R., E.O., M.C., C.C., A.S., M.S., A.D., and V.N. contributed unpublished reagents/analytic tools; U.V., R.V., G.S.P., and A.F. analyzed data; U.V., R.V., G.S.P., M.I., and A.F. wrote the paper.

*U.V., R.V., and G.S.P. contributed equally to this work.