非诺贝特对全脑缺血/再灌注损伤大鼠的保护作用

目的探讨非诺贝特对大鼠全脑缺血/再灌注损伤(I/R)的保护作用及机制。方法采用双侧颈总动脉夹闭合并低血压方法建立全脑缺血/再灌注大鼠模型。药物非诺贝特(fenofibrate,FF;33、100、300mg.kg-1)在缺血前30min灌胃给药,PPARα受体拮抗剂MK886(6mg.kg-1)在给予非诺贝特300mg.kg-1前腹腔注射。Morris水迷宫测定大鼠空间学习能力变化,病理切片HE染色观察海马神经元形态结构变化,免疫组化染色检测海马组织核转录因子NF-κBp65蛋白的表达,生化酶学方法观察超氧歧化酶(SOD)活性、丙二醛(MDA)含量变化,酶联免疫吸附法(ELISA)检测细胞因子IL-1β、IL-6、IL-10、TNF-α含量变化。结果非诺贝特能明显缩短全脑缺血/再灌注大鼠的寻台潜伏期,减轻全脑缺血/再灌注大鼠海马神经元损伤,降低海马神经元NF-κB p65蛋白表达,明显阻遏缺血/再灌注大鼠海马IL-1β、IL-6、TNF-α、MDA含量的升高和IL-10含量及SOD活性的降低;预先给予MK886能取消非诺贝特的作用。结论非诺贝特对缺血/再灌注脑损伤有明显保护作用,其机制与激活PPARα,抑制NF-κB活性,抑制CNS炎症反应和氧化应激有关。

Effects of fenofibrate on global cerebral ischemia/reperfusion injury in rats

Aim To investigate the effect of fenofibrate on focal cerebral ischemia injury in rats and its mechanism.Methods The rat model of global cerebral ischemia/reperfusion injury was established by bilateral common carotid arteries occlusion combined with hemorrhagic hypotension.Fenofibrate (33, 100, 300 mg·kg~(-1)) was intragastriclly administered 30 min before the operation, MK886 (6 mg·kg~(-1)) was given intraperitoneally 30 min before administration of fenofibrate (300 mg·kg~(-1)).Morris water maze was used to evaluate the ability of spatial learning and memory function.HE staining was used to observe pathological morphological changes of hippocampal neurons. NF-κBp65 expression was detected by immunohistochemistry, SOD activities and MDA contents were analyzed by biochemistry, and IL-1β, IL-6, IL-10, TNF-α levels were detected by ELISA.Results Fenofibrate remarkably improved the spatial learning and memory function, obviously prevented the hippocampal neurons from karyopycnosis and losing induced by I/R. Fenofibrate significantly blunted the increase of MDA, NF-κBp65, TNF-α, IL-1β, IL-6, and the decrease of IL-10 and SOD activities of I/R rats.Conclusions Fenofibrate has an obviously neuroprotective effect on global cerebral ischemia/reperfusion damage by activating PPARα.The anti-inflammation and antioxidative stress of fenofibrate may be involved in the protective mechanism.