1. Peroxisome proliferator-activated receptor-α activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment
- Author
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Olivier Pétrault, Bernard Dupuis, Isabelle Six, Régis Bordet, Patrick Gelé, Christophe Furman, Bart Staels, Dominique Deplanque, Roméo Cecchelli, Patrick Duriez, Muriel Bouly, Didier Leys, Jean-Charles Fruchart, Stéphane Nion, Université Lille 2 - Faculté de Médecine, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs nucléaires, lipoprotéines et athérosclérose, Institut Pasteur de Lille, 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, Droit et Santé, Réseau International des Instituts Pasteur (RIIP), Université d'Artois (UA), Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (LBHE), P.G. was supported by a grant from 'Conseil Régional Nord Pas de Calais et Centre Hospitalier Régional et Universitaire de Lille. ' This work was supported by grants from ' Génopole Lille Nord-Pas de Calais '(#01360124) and Institut National de la Santé et de la Recherche Médicale (CReS4CR02F)., and We thank Alexandra Tavernier-Sommerville for her assistance with the English version of this paper.
- Subjects
Middle Cerebral Artery ,Mouse ,Nitric Oxide Synthase Type II ,Receptors, Cytoplasmic and Nuclear ,Peroxisome proliferator-activated receptor ,medicine.disease_cause ,Rats, Inbred WKY ,Mice ,0302 clinical medicine ,Fenofibrate ,Mice, Knockout ,chemistry.chemical_classification ,0303 health sciences ,biology ,General Neuroscience ,Infarction, Middle Cerebral Artery ,Cerebral Infarction ,Intercellular Adhesion Molecule-1 ,Neuroprotection ,Vasodilation ,Nitric oxide synthase ,Stroke ,Neuroprotective Agents ,Cerebrovascular Circulation ,Middle cerebral artery ,medicine.symptom ,medicine.drug ,PPAR-α ,medicine.medical_specialty ,Adhesion proteins ,Nitric Oxide Synthase Type III ,Development/Plasticity/Repair ,Ischemia ,Vascular Cell Adhesion Molecule-1 ,Mice, Transgenic ,Inflammation ,Time ,03 medical and health sciences ,Apolipoproteins E ,medicine.artery ,Internal medicine ,medicine ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,business.industry ,Prevention ,medicine.disease ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Oxidative stress ,biology.protein ,Nitric Oxide Synthase ,business ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
International audience; The treatment of ischemic strokes is limited to the prevention of cerebrovascular risk factors and to the modulation of the coagulation cascade during the acute phase. Anew therapeutic strategy could be to preventively protect the brain against noxious biological reactions induced by cerebral ischemia such as oxidative stress and inflammation to minimize their neurological consequences. Here, we show that a peroxisome proliferator-activated receptor (PPAR-α) activator, fenofibrate, protects against cerebral injury by anti-oxidant and antiinflammatory mechanisms. A 14 d preventive treatment with fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice as well as decreases cerebral infarct volume in C57BL/6 wild-type mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-α-deficient mice, suggesting that PPAR-α activation is involved as a mechanism of the protection against cerebral injury. Furthermore, this neuroprotective effect appears independently of any improvement in plasma lipids or glycemia and is associated with (1) an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation unrelated to an increase in nitric oxide synthase (NOS) type III expression, (2) a decrease in cerebral oxidative stress depending on the increase in numerous antioxidant enzyme activities, and (3) the prevention of ischemia-induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in cerebral vessels without any change in NOS II expression. These data demonstrate that PPAR-α could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-α activators could preventively decrease the severity of stroke in humans.
- Published
- 2003