Acute treatment by a PPAR-α agonist decreases cerebral infarct volume and prevents post-ischemic endothelium and Kir 2.1 impairment

Introduction

Chronic pre-treatment by Peroxysome Proliferator-Activated Receptor-á agonist induces a neuroprotective effect in experimental model of focal cerebral ischemia by both anti-inflammatory and anti-oxidant mechanisms ¹ . The aim of our study is to demonstrate if an acute activation of PPAR-α could also induce cerebral protection during cerebral ischemia as well as a prevention of post-ischemic endothelium and Kir 2.1 smooth muscle impairment, which are mediated by oxidative stress.

Materials

Male Wistar rats were subjected to a 60 minutes middle cerebral artery occlusion (MCAo). Vehicle or fenofibrate (50 or 200 mg/kg per day), a PPAR-α activator, was administered by gavage twice a day during 72 hours after onset of ischemia. The infarct volume was determined at 72 hours of reperfusion. The ipsilateral MCA was removed and mounted in a small vessel arteriograph. The endothelium and smooth muscle reactivity was then studied.

Results

Fenofibrate at 50 and 200 mg/kg induced a significant decrease in infarct volume by 21% and 32%, respectively (p<0.05 versus vehicle). Acute administration of fenofibrate at 50 mg/kg prevented the ischemia/reperfusion-impairment of endothelium relaxation (21.6±5.0% versus 12.9±2.9%, p<0.05) but not at 200 mg/kg (9.8±1.8%, NS). KCl-induced smooth muscle relaxation was reduced in ischemic animals compared to control (12.1±1.5% versus 26.0±2.4%, p<0.05) whereas fenofibrate administration at 50 mg/kg prevented the post-ischemic impairment of smooth muscle Kir 2.1 relaxation (22.6±2.9%, p<0.05 versus ischemic animals) and not at 200 mg/kg (14.8±4.4%, NS versus ischemic animals). Endothelium-independent relaxation to sodium nitroprusside was similar in all groups.

Conclusion

Acute administration of PPAR-α agonist induces a significant neuroprotection. But our results show also a discrepancy between the neuroprotection and the vasculoprotection level according to the dose, suggesting that the vascular wall should not be considered as the only pharmacological target in the treatment of stroke.