EA1046, Département de Pharmacologie médicale, Institut de Médecine Prédictive et de Recherche Thérapeutique, Lille Nord of France University, Faculté de Médecine; Centre Hospitalier Universitaire, Lille, France.
Vascul Pharmacol. 2009 Nov-Dec;51(5-6):323-30. doi: 10.1016/j.vph.2009.08.002. Epub 2009 Sep 2.
To explore the mechanisms of action of preventive neuroprotection induced by PPAR-alpha 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preventive treatment with fenofibrate up until the induction of experimental brain ischaemia and fenofibrate treatment withdrawn 3days before ischaemia induction. Fenofibrate (200mg/kg/day) was administered in rats for 14days or withdrawn 3days before induction of cerebral ischaemia. Animals underwent a 1-hour middle cerebral artery occlusion (MCAo), followed by reperfusion for 24h. 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 3days 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.
为了探索过氧化物酶体增殖物激活受体-α（PPAR-α）激活诱导预防性神经保护的作用机制，我们评估了给予非诺贝特进行预防性治疗直至实验性脑缺血诱导以及缺血诱导前 3 天停药对神经元和血管的影响。非诺贝特（200mg/kg/天）以 14 天剂量给药或在诱导脑缺血前 3 天停药，给大鼠用药。动物接受 1 小时大脑中动脉闭塞（MCAo），随后再灌注 24 小时。分析 MCA 的血管反应性，并使用脑切片评估梗死面积、炎症和氧化应激标志物。非诺贝特给药显著减少脑梗死体积。这种作用与部分预防缺血后内皮功能障碍有关。然而，在诱导缺血前 3 天停药会降低神经保护作用，并且在预防内皮功能障碍和超氧阴离子产生方面效果较差。相比之下，非诺贝特以相似的程度显著减少缺血区小胶质细胞激活和中性粒细胞浸润。我们的结果表明，非诺贝特诱导的脑保护作用可能与急性作用和预适应样机制有关。血管保护作用似乎更能转化非诺贝特给药的急性作用。
