1. Peroxisome proliferator-activated receptor-α activation protects brain capillary endothelial cells from oxygen-glucose deprivation-induced hyperpermeability in the blood-brain barrier
- Author
-
Mysiorek, Caroline, Culot, Maxime, Dehouck, Lucie, Derudas, Bruno, Staels, Bart, Bordet, Régis, Cecchelli, Roméo, Tilloy-Fenart, Laurence, Berezowski, Vincent, Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), CELLIAL Technologies, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine predictive et de recherche thérapeutique (IMPRT), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Université de Lille-UNICANCER-Université de Lille-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
- Subjects
Time Factors ,MESH: Neuroglia/physiology ,MESH: Neuroglia/drug effects ,MESH: Blood-Brain Barrier/metabolism ,Ischaemia ,MESH: Mice, Knockout ,MESH: Animals, Newborn ,MESH: Dose-Response Relationship, Drug ,Mice ,MESH: Cell Proliferation/drug effects ,Fenofibrate ,MESH: PPAR alpha/deficiency ,MESH: von Willebrand Factor/immunology ,MESH: Animals ,Claudin-5 ,Hypoxia ,MESH: Claudin-5 ,MESH: Fenofibrate/analogs & derivatives ,Cells, Cultured ,Hypolipidemic Agents ,Blood-brain barrier ,Mice, Knockout ,MESH: Endothelial Cells/drug effects ,MESH: Hypolipidemic Agents/pharmacology ,Brain ,MESH: Coculture Techniques/methods ,Neuroprotection ,MESH: von Willebrand Factor/metabolism ,Neuroglia ,MESH: Cells, Cultured ,MESH: PPAR alpha/metabolism ,MESH: Capillary Permeability/physiology ,MESH: Brain/cytology ,Capillary Permeability ,In vitro model ,MESH: Hypoxia/prevention & control ,MESH: Mice, Inbred C57BL ,Peroxisome Proliferator-activated receptor-alpha ,MESH: Fenofibrate/pharmacology ,von Willebrand Factor ,MESH: Capillary Permeability/drug effects ,Animals ,MESH: Membrane Proteins/metabolism ,PPAR alpha ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Endothelium ,MESH: Mice ,Cell Proliferation ,MESH: Hypoxia/pathology ,Dose-Response Relationship, Drug ,MESH: Gene Expression Regulation/genetics ,MESH: Time Factors ,Endothelial Cells ,Membrane Proteins ,MESH: Gene Expression Regulation/drug effects ,Coculture Techniques ,MESH: Capillary Permeability/genetics ,Mice, Inbred C57BL ,Glucose ,Animals, Newborn ,Gene Expression Regulation ,nervous system ,MESH: Blood-Brain Barrier/physiology ,MESH: Endothelial Cells/metabolism ,MESH: Glucose/deficiency - Abstract
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.
- Published
- 2009