Glutamate-Mediated Blood–Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery
- Udi Vazana1,2,3,*,
- Ronel Veksler1,2,*,
- Gaby S. Pell4,5,*,
- Ofer Prager1,2,
- Michael Fassler1,2,3,
- Yoash Chassidim1,2,
- Yiftach Roth5,
- Hamutal Shahar4,5,
- Abraham Zangen4,
- Ruggero Raccah6,
- Emanuela Onesti7,
- Marco Ceccanti7,
- Claudio Colonnese8,
- Antonio Santoro8,
- Maurizio Salvati8,
- Alessandro D'Elia8,
- Valter Nucciarelli8,
- Maurizio Inghilleri7, and
- Alon Friedman1,2,9
- 1Departments of Cognitive and Brain Sciences,
- 2Physiology and Cell Biology,
- 3Biomedical Engineering, and
- 4Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, 84105 Israel,
- 5Brainsway, Jerusalem, 9777518 Israel,
- 6Atid, Rome 00187, Italy,
- 7Departments of Neurology and Psychiatry and
- 8Neurological Sciences, Sapienza University of Rome, Rome 00185, Italy, and
- 9Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
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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U.V., R.V., O.P., M.F., Y.C., Y.R., H.S., A.Z., R.R., E.O., M.C., C.C., A.S., M.S., A.D., and V.N. contributed unpublished reagents/analytic tools; U.V., R.V., G.S.P., and A.F. analyzed data; U.V., R.V., G.S.P., M.I., and A.F. wrote the paper.
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↵*U.V., R.V., and G.S.P. contributed equally to this work.
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.
- Received February 18, 2016.
- Revision received May 31, 2016.
- Accepted June 6, 2016.
- Copyright © 2016 the authors 0270-6474/16/367727-13$15.00/0
