Abstract
NXY-059, a polar compound with limited transport across the blood-brain barrier, has demonstrated neuroprotection in several animal models of acute ischemic stroke but failed to confirm clinical benefit in the second phase III trial (SAINT-II). To improve the understanding of the mechanisms responsible for its neuroprotective action in preclinical models a series of experiments was carried out in an in vitro blood-brain barrier (BBB) model. A clinically attainable concentration of 250 mumol/L of NXY-059 administered at the onset or up to 4 h after oxygen glucose deprivation (OGD) produced a significant reduction in the increased BBB permeability caused by OGD. Furthermore, OGD produced a huge influx of tissue plasminogen activator across the BBB, which was substantially reduced by NXY-059. This study suggests that the neuroprotective effects of NXY-059 preclinically, may at least in part be attributed to its ability to restore functionality of the brain endothelium.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzenesulfonates / administration & dosage
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Benzenesulfonates / pharmacokinetics
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Benzenesulfonates / pharmacology*
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Blood-Brain Barrier / drug effects*
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Blood-Brain Barrier / physiopathology
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Brain / blood supply
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Brain / drug effects
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Brain / physiopathology
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Capillaries / drug effects
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Capillaries / physiopathology
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Capillary Permeability / drug effects
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Capillary Permeability / physiology
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Cattle
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Cell Hypoxia / drug effects
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Cells, Cultured
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Endothelial Cells / drug effects
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Endothelial Cells / physiology
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Glucose / deficiency
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Membrane Proteins / metabolism
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Neuroglia / drug effects
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Neuroglia / physiology
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / pharmacology*
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Occludin
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Rats
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Rats, Sprague-Dawley
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Sucrose / metabolism
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Tight Junctions / drug effects
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Tight Junctions / physiology
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Time Factors
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Tissue Plasminogen Activator / metabolism
Substances
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Benzenesulfonates
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Membrane Proteins
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Neuroprotective Agents
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Occludin
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Ocln protein, rat
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Sucrose
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disufenton sodium
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Tissue Plasminogen Activator
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Glucose