title: Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery.
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.
  
  
  
  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.
authors.affiliation: Departments of Cognitive and Brain Sciences, Physiology and Cell Biology, Biomedical Engineering, and.
authors.forename: Udi
authors.initials: U
authors.lastname: Vazana
authors.affiliation: Departments of Cognitive and Brain Sciences, Physiology and Cell Biology.
authors.forename: Ronel
authors.initials: R
authors.lastname: Veksler
authors.affiliation: Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, 84105 Israel, Brainsway, Jerusalem, 9777518 Israel.
authors.forename: Gaby S
authors.initials: GS
authors.lastname: Pell
authors.affiliation: Departments of Cognitive and Brain Sciences, Physiology and Cell Biology.
authors.forename: Ofer
authors.initials: O
authors.lastname: Prager
authors.affiliation: Departments of Cognitive and Brain Sciences, Physiology and Cell Biology, Biomedical Engineering, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Fassler
authors.affiliation: Departments of Cognitive and Brain Sciences, Physiology and Cell Biology.
authors.forename: Yoash
authors.initials: Y
authors.lastname: Chassidim
authors.affiliation: Brainsway, Jerusalem, 9777518 Israel.
authors.forename: Yiftach
authors.initials: Y
authors.lastname: Roth
authors.affiliation: Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, 84105 Israel, Brainsway, Jerusalem, 9777518 Israel.
authors.forename: Hamutal
authors.initials: H
authors.lastname: Shahar
authors.affiliation: Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, 84105 Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Zangen
authors.affiliation: Atid, Rome 00187, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Raccah
authors.affiliation: Departments of Neurology and Psychiatry and.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Onesti
authors.affiliation: Departments of Neurology and Psychiatry and.
authors.forename: Marco
authors.identifier: 0000-0001-8897-3736
authors.initials: M
authors.lastname: Ceccanti
authors.affiliation: Neurological Sciences, Sapienza University of Rome, Rome 00185, Italy, and.
authors.forename: Claudio
authors.identifier: 0000-0003-4249-4689
authors.initials: C
authors.lastname: Colonnese
authors.affiliation: Neurological Sciences, Sapienza University of Rome, Rome 00185, Italy, and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Neurological Sciences, Sapienza University of Rome, Rome 00185, Italy, and.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Salvati
authors.affiliation: Neurological Sciences, Sapienza University of Rome, Rome 00185, Italy, and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: D'Elia
authors.affiliation: Neurological Sciences, Sapienza University of Rome, Rome 00185, Italy, and.
authors.forename: Valter
authors.identifier: 0000-0002-4728-8334
authors.initials: V
authors.lastname: Nucciarelli
authors.affiliation: Departments of Neurology and Psychiatry and.
authors.forename: Maurizio
authors.identifier: 0000-0001-5365-3417
authors.initials: M
authors.lastname: Inghilleri
authors.affiliation: Departments of Cognitive and Brain Sciences, Physiology and Cell Biology, Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada alon.friedman@dal.ca.
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
mesh_terms: D015761:4-Aminopyridine / Q000633:toxicity; D000328:Adult; D000368:Aged; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects*; D001932:Brain Neoplasms / Q000150:complications; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D005909:Glioblastoma / Q000150:complications; D018698:Glutamic Acid / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010539:Permeability / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced; D020521:Stroke / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D018698:Glutamic Acid; D015761:4-Aminopyridine
keywords: N-methyl-d-aspartate; blood–brain barrier; glutamate; imaging; transcranial magnetic stimulation