Cerebrovascular protection as a possible mechanism for the protective effects of NXY-059 in preclinical models: an in vitro study.

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.

• Authors: Maxime Culot, Caroline Mysiorek, Mila Renftel, Benoit D Roussel, Yannick Hommet, Denis Vivien, Roméo Cecchelli, Laurence Fenart, Vincent Berezowski, Marie-Pierre Dehouck, Stefan Lundquist
• Journal: Brain research (Brain Res) Vol. 1294 Pg. 144-52 (Oct 19 2009) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 19631615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzenesulfonates
• Membrane Proteins
• Neuroprotective Agents
• Occludin
• Ocln protein, rat
• Sucrose
• disufenton sodium
• Tissue Plasminogen Activator
• Glucose

Topics

• Animals
• Benzenesulfonates (administration & dosage, pharmacokinetics, pharmacology)
• Blood-Brain Barrier (drug effects, physiopathology)
• Brain (blood supply, drug effects, physiopathology)
• Capillaries (drug effects, physiopathology)
• Capillary Permeability (drug effects, physiology)
• Cattle
• Cell Hypoxia (drug effects)
• Cells, Cultured
• Endothelial Cells (drug effects, physiology)
• Glucose (deficiency)
• Membrane Proteins (metabolism)
• Neuroglia (drug effects, physiology)
• Neuroprotective Agents (administration & dosage, pharmacokinetics, pharmacology)
• Occludin
• Rats
• Rats, Sprague-Dawley
• Sucrose (metabolism)
• Tight Junctions (drug effects, physiology)
• Time Factors
• Tissue Plasminogen Activator (metabolism)