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

Journal: The Journal of Neuroscience 36(29):7727–7739 (2016)

Authors: U Vazana, R Veksler, G.S Pell, O Prager, M Fassler, Y Chassidim, Y Roth, H Shahar, A Zangen, R Raccah, E Onesti, M Ceccanti, C Colonnese, A Santoro, M Salvati, A D’Elia, V Nucciarelli, M Inghilleri, A Friedman


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.


The goal of this study was to demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeabilityin vivo.


Using intravital microscopyand ECoG recording, the authors tested whether focally induced cortical seizures are associated with increased vascular permeability in the rat cerebral cortex.To test whether the increase in endothelial permeability was attributed to NMDA receptors, experiments were repeated with cortical perfusion of NMDA and with glutamate in the presence of an NMDA receptor antagonist. The authors then tested whether release of glutamate associated with neuronal activation using rTMS could increase barrier permeability and facilitate drug delivery into the brain. Finally, based on their pre-clinical experiments, the authors 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.


The authors 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. Furthermore, the study demonstrates the safety of stimulation that efficiently increased blood–brain barrier permeability in 10 of 15 patients with malignantglial tumors.


This study suggests a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders.

Read full article