CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis

Basuroy, Shyamali; Leffler, Charles W.; Parfenova, Helena

doi:10.1152/ajpcell.00023.2013

Cited by 49 publications

(42 citation statements)

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“…Rat brain endothelial cells, astrocytes and pericytes were treated with kainate (213 Da; 100 mM stock solution was prepared in sterile water by the addition of NaOH) at 10 µM and 100 µM concentrations in culture medium for 1 and 24 h, based on our preliminary experiment and in agreement with literature data [32]. Simvastatin, edaravone (for both 1 mM stock solution was prepared in dimethyl sulfoxide) and dexamethasone (cyclodextrin complex; 10 mM stock solution was prepared in sterile water) were applied at a concentration of 1 µM based on our preliminary study and literature data [21,23,25].…”

Section: Treatmentsmentioning

confidence: 70%

“…Excitotoxicity is one of the main pathological pathways in CNS diseases leading to both neuronal injury and BBB dysfunction [5,42]. Glutamate was shown to increase BBB permeability and reduce the integrity of tight junctions in culture models of the BBB [8,32,43]. Ionotropic glutamate receptor agonists NMDA and AMPA were also described to decrease resistance and increase permeability of porcine brain endothelial cells [32].…”

Section: Discussionmentioning

confidence: 99%

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Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Barna

Walter

Harazin

et al. 2020

Fluids Barriers CNS

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Background: Excitotoxicity is a central pathological pathway in many neurological diseases with blood-brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes.Methods: Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR.Results: Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment. Conclusion:Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Treatmentsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Barna

Walter

Harazin

et al. 2020

Fluids Barriers CNS

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“…The strongest area of development in terms of understanding potential roles for these receptors is in the area of blood-brain barrier (BBB) function. While uncontrolled glutamate levels in brain are toxic to neurons, they are also likely to damage endothelial function and disrupt BBB integrity [20, 66,67]. There are indications that these endothelial effects are mediated by NMDARs and are related to altered expression of efflux transporters [68] and to reduced expression and redistribution of tight junction proteins [20], culminating in dramatically impaired barrier integrity [18] and transmigration of immune cells into the brain [31].…”

Section: Nmdars In Brain Endothelial Cell Physiologymentioning

confidence: 99%

Physiological Roles of Non-Neuronal NMDA Receptors

Hogan-Cann

Anderson

2016

Trends in Pharmacological Sciences

123

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“…So in the context of stroke and brain injury, excitotoxicity mechanisms should operate in multiple cell types. Besides astrocytes and oligodendrocytes, glutamate transporters also exist in pericytes [35], and over-activation of ionotropic glutamate channels can trigger apoptosis in cerebral endothelium as well [36, 37]. Excitotoxic cascades are not only a neuronal phenomenon but comprise all compartments in the neurovascular unit.…”

Section: Excitotoxicitymentioning

confidence: 99%

Mechanisms of Neurovascular Dysfunction in Acute Ischemic Brain

Terasaki¹,

Liu²,

Hayakawa³

et al. 2014

CMC

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The neurovascular unit is now well accepted as a conceptual framework for investigating the mechanisms of ischemic stroke. From a molecular and cellular perspective, three broad mechanisms may underlie stroke pathophysiology – excitotoxicity, oxidative stress and inflammation. To date, however, most investigations of these basic mechanisms have focused on neuronal responses. In this mini-review, we ask whether these mechanisms of excitotoxicity, oxidative stress and inflammation can also be examined in terms of non-neuronal interactions in the neurovascular unit, including the release of extracellular vesicles for cell-cell signaling.

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CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis

Abstract: Basuroy S, Leffler CW, Parfenova H. CORM-A1 prevents bloodbrain barrier dysfunction caused by ionotropic glutamate receptormediated endothelial oxidative stress and apoptosis.

Cited by 49 publications

References 48 publications

Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Physiological Roles of Non-Neuronal NMDA Receptors

Mechanisms of Neurovascular Dysfunction in Acute Ischemic Brain

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