PPARα is involved in the multitargeted effects of a pretreatment with atorvastatin in experimental stroke

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 PPAR alpha 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 (10mg/kg/day) on C57Bl6 wild-type and PPAR alpha-KO mice submitted to experimental stroke. PPAR alpha 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 PPAR alpha. The decrease in IL-6 plasmatic levels was PPAR alpha 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 PPAR alpha 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 PPAR alpha status. At the vascular level, we found that the atorvastatin-related endothelial nitric oxide synthase upregulation was regulated by PPAR alpha in the aorta, while there was no effect in the brain. We demonstrate here that PPAR alpha is a key mediator of the multitargeted neuroprotective effects of statins in stroke.