title: PPARα is involved in the multitargeted effects of a pretreatment with atorvastatin in experimental stroke.
abstract: There is now substantial data in the literature showing that statins can protect against cerebral ischemia. This neuroprotective potency is related to their pleiotropic effects that modulate various pathways implicated in the pathophysiology of stroke. It has been demonstrated that statins exert anti-inflammatory and vasculoprotective effects, thus contributing to a reduction in infarct size. The underlying mechanisms are still incompletely known. As a cross-talk between statins and the nuclear receptor PPARα has been described, we hypothesized that this cross-talk is necessary to neuroprotection in stroke. We studied the effects of a 14-day preventive atorvastatin treatment (10 mg/kg/day) on C57Bl6 wild-type and PPARα-KO mice submitted to experimental stroke. PPARα was involved in the atorvastatin-induced neuroprotective effect, as confirmed by the measurement of infarct volumes. We also evidenced that the anti-inflammatory action of atorvastatin is mediated, at least partly, by PPARα. The decrease in IL-6 plasmatic levels was PPARα dependent. The cerebral expression of the adhesion molecules ICAM-1 and vascular cell adhesion molecule was reduced by the atorvastatin treatment, and this effect was PPARα dependent in the cortex but not in the striatum of treated animals. Atorvastatin also diminished the cerebral expression of iNOS in the cortex, but had no effect in the striatum of treated mice, whatever the PPARα status. At the vascular level, we found that the atorvastatin-related endothelial nitric oxide synthase upregulation was regulated by PPARα in the aorta, while there was no effect in the brain. We demonstrate here that PPARα is a key mediator of the multitargeted neuroprotective effects of statins in stroke.
authors.affiliation: Department of Medical Pharmacology, EA 1046, University of Lille Nord de France, UDSL, Faculty of Medicine, Lille University Hospital, Lille, France.
authors.forename: Thavarak
authors.initials: T
authors.lastname: Ouk
authors.forename: Camille
authors.initials: C
authors.lastname: Potey
authors.forename: Maud
authors.initials: M
authors.lastname: Laprais
authors.forename: Sophie
authors.initials: S
authors.lastname: Gautier
authors.forename: Rémi
authors.initials: R
authors.lastname: Hanf
authors.forename: Raphaël
authors.initials: R
authors.lastname: Darteil
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; D000069059:Atorvastatin; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008055:Lipids / Q000097:blood; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D020521:Stroke / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D015850:Interleukin-6; D008055:Lipids; D018696:Neuroprotective Agents; D047493:PPAR alpha; D011758:Pyrroles; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000069059:Atorvastatin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: PPARalpha; statin; stroke