Molecular analysis for ischemic tolerance of neuron

缺血性脑神经元的死亡与存活机制是神经科学研究的热点之一。近年来的研究强调了线粒体在缺血性神经元损伤中的重要作用，线粒体功能障碍可诱导坏死和细胞凋亡。另一方面，缺血应激诱导神经元的缺血耐受已有报道，但缺血耐受的分子机制尚未阐明。本研究采用沙鼠短暂性前脑缺血、3-硝基丙酸致大鼠纹状体损伤、大鼠永久性大脑中动脉闭塞、大鼠暂时性大脑中动脉闭塞、小鼠永久性大脑中动脉闭塞等脑缺血模型，探讨线粒体功能与凋亡的关系及缺血耐受机制。我们在模型a和b中证实细胞凋亡参与神经元死亡，在模型b和c中证实细胞凋亡相关基因和聚adp -核糖基化参与神经元损伤，在模型c和d中证实缺血半暗区神经元显著诱导硫氧还蛋白，在模型a和e中证实3-硝基丙酸化学预处理和过表达硫氧还蛋白可诱导缺血耐受。

The mechanisms of neuronal death and survival in ischemic brain are one of major topics in neuroscience. Recent papers have stressed the important role of mitochondria in ischemic neuronal damage in that both necrosis and apoptosis are induced by the dysfunction of mitochondria. On the other hand, the induction of ischemic tolerance in neuron after ischemic stress has been reported, but the molecular mechanisms of ischemic tolerance have not been elucidated. In the present study, we used several cerebral ischemic models including a. transient forebrain ischemia in gerbil, b. 3-nitropropionic acid-induced striatal damage in rat, c. permanent middle cerebral artery occlusion in rat, d. transient middle cerebral artery occlusion in rat, e. permanent middle cerebral artery occlusion in mouse in order to examine the relation of mitochondrial function and apoptosis and the mechanism of ischemic tolerance. We have demonstrated that apoptosis was involved in neuronal death in model a and b, that apoptosis related genes and poly(ADP-ribosyl)ation was involved in neuronal damage in model b and c, that thioredoxin is markedly induced in neuron in ischemic penumbra in model c and d, and that chemical preconditioning with 3-nitropropionic acid and overexpression of thioredoxin can induce ischemic tolerance in model a and e.