Peroxisome-proliferator-activated receptor-alpha activation protects brain capillary endothelial cells from oxygen-glucose deprivation-induced hyperpermeability in the blood-brain barrier.
That promising neuroprotectants failed to demonstrate benefit against stroke highlights the great difficulties to translate preclinical pharmacological effects in clinical outcomes. Part of this hurdle implies the complex response to injury of the neurovascular unit increasing the cerebrovascular permeability at the level of the blood-brain barrier (BBB). Previous studies reported neuroprotection in animal models upon activation of the nuclear receptor PPARalpha(peroxisome proliferator-activated receptor)alpha, but the cellular targets at the BBB level remain largely unexplored. Here, to study whether PPAR-alpha activation acts on BBB permeability, we adapted a mouse BBB cell model to ischaemic conditions at the stage of occlusion defined in vitro as oxygen-glucose deprivation (OGD). This model consists of a co-culture of brain capillary endothelial cells (ECs) on a filter insert placed upon a rat glial cell culture. The EC monolayer permeability increase induced by 4 h of OGD was significantly restricted after treatment with the PPAR-alpha agonist fenofibric acid (FA) 24 h before or at the onset of OGD. Treatments of separated ECs or glial cells showed that this protective effect was conferred by BBB ECs but not glial cells. Furthermore, co-cultures with ECs from PPAR-alpha-deficient mice revealed that FA had no effect on OGD-induced hyperpermeability. No transcriptional modulation of classical PPAR-alpha target genes such as SOD, ICAM-1, VCAM-1, ACO, CPT-1, PDK-4 or ET-1 was observed in wild type mouse ECs. In conclusion, these results suggest that part of the preventive PPAR-alpha-mediated protection may occur via BBB ECs by limiting hyperpermeability.
Mysiorek
Caroline
C
Univ Lille Nord de France, Lille, France.
Culot
Maxime
M
Dehouck
Lucie
L
Derudas
Bruno
B
Staels
Bart
B
Bordet
Régis
R
Cecchelli
Roméo
R
Fenart
Laurence
L
Berezowski
Vincent
V
D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000502:physiology*; D001921:Brain / Q000166:cytology*; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D062507:Claudin-5; D018920:Coculture Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000172:deficiency*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D000860:Hypoxia / Q000473:pathology / Q000517:prevention & control; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D047493:PPAR alpha / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors; D014841:von Willebrand Factor / Q000276:immunology / Q000378:metabolism
D062507:Claudin-5; C491511:Cldn5 protein, mouse; D000960:Hypolipidemic Agents; D008565:Membrane Proteins; D047493:PPAR alpha; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; C006012:fenofibric acid; D005947:Glucose; D011345:Fenofibrate