Cerebrovascular protection as a possible mechanism for the protective effects of NXY-059 in preclinical models: an in vitro study.
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.
Culot
Maxime
M
Univ Lille-Nord de France, F59000 Lille, France. maxime.culot@univ-artois.fr
Mysiorek
Caroline
C
Renftel
Mila
M
Roussel
Benoit D
BD
Hommet
Yannick
Y
Vivien
Denis
D
Cecchelli
Roméo
R
Fenart
Laurence
L
Berezowski
Vincent
V
Dehouck
Marie-Pierre
MP
Lundquist
Stefan
S
D000818:Animals; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D008565:Membrane Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D062793:Occludin; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D001557:Benzenesulfonates; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D062793:Occludin; C568987:Ocln protein, rat; D013395:Sucrose; C120851:disufenton sodium; D010959:Tissue Plasminogen Activator; D005947:Glucose