Abstract
To explore the mechanisms of action of preventive neuroprotection induced by PPAR-α activation, we have evaluated the neuronal, vascular effects of preventive treatment with fenofibrate up until the induction of experimental brain ischaemia and fenofibrate treatment withdrawn 3 days before ischaemia induction. Fenofibrate (200 mg/kg/day) was administered in rats for 14 days or withdrawn 3 days before induction of cerebral ischaemia. Animals underwent a 1-hour middle cerebral artery occlusion (MCAo), followed by reperfusion for 24 h. The MCA's vasoreactivity was analyzed and brain sections were used to assess infarct size, inflammatory and oxidative stress markers. Fenofibrate administration significantly decreases the cerebral infarct volume. This effect was associated with partial prevention of post-ischaemic endothelial dysfunction. However, withdrawal of the fenofibrate treatment 3 days before the induction of ischaemia reduced the neuroprotection and was less beneficial in preventing endothelial dysfunction as well as superoxide anion production. In contrast, fenofibrate significantly reduced microglial activation and neutrophil infiltration into the ischaemic zone to a similar extent in both treatment modes. Our results show that the fenofibrate-induced cerebral protective effect may be related to both an acute effect and a preconditioning-like mechanism. The vascular protective effect appears rather to translate the acute effects of fenofibrate administration.
Published Version
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