RT Journal Article
SR Electronic
T1 Glutamate-Mediated Blood–Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7727
OP 7739
DO 10.1523/JNEUROSCI.0587-16.2016
VO 36
IS 29
A1 Udi Vazana
A1 Ronel Veksler
A1 Gaby S. Pell
A1 Ofer Prager
A1 Michael Fassler
A1 Yoash Chassidim
A1 Yiftach Roth
A1 Hamutal Shahar
A1 Abraham Zangen
A1 Ruggero Raccah
A1 Emanuela Onesti
A1 Marco Ceccanti
A1 Claudio Colonnese
A1 Antonio Santoro
A1 Maurizio Salvati
A1 Alessandro D'Elia
A1 Valter Nucciarelli
A1 Maurizio Inghilleri
A1 Alon Friedman
YR 2016
UL http://www.jneurosci.org/content/36/29/7727.abstract
AB 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.