title: Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment.
abstract: 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. A new 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-alpha) activator, fenofibrate, protects against cerebral injury by anti-oxidant and anti-inflammatory 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-alpha-deficient mice, suggesting that PPAR-alpha 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-alpha could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-alpha activators could preventively decrease the severity of stroke in humans.
authors.affiliation: Laboratoire de Pharmacologie, Université de Lille 2, Faculté deMédecine, Lille, 59045 France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Deplanque
authors.forename: Patrick
authors.initials: P
authors.lastname: Gelé
authors.forename: Olivier
authors.initials: O
authors.lastname: Pétrault
authors.forename: Isabelle
authors.initials: I
authors.lastname: Six
authors.forename: Christophe
authors.initials: C
authors.lastname: Furman
authors.forename: Muriel
authors.initials: M
authors.lastname: Bouly
authors.forename: Stéphane
authors.initials: S
authors.lastname: Nion
authors.forename: Bernard
authors.initials: B
authors.lastname: Dupuis
authors.forename: Didier
authors.initials: D
authors.lastname: Leys
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
authors.forename: Roméo
authors.initials: R
authors.lastname: Cecchelli
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Patrick
authors.initials: P
authors.lastname: Duriez
authors.forename: Régis
authors.initials: R
authors.lastname: Bordet
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013995:Time; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D018696:Neuroprotective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D011345:Fenofibrate