Demougeot C, Van Hoecke M, Bertrand N, Prigent-Tessier A, Mossiat C, Beley A, Marie C
Laboratoire de Pharmacodynamie et Physiologie Pharmaceutique (L3P), Faculté de Pharmacie, 7, Bd Jeanne d'Arc, BP 87900, 21079 Dijon Cedex, France.
J Pharmacol Exp Ther. 2004 Dec;311(3):1080-7. doi: 10.1124/jpet.104.072744. Epub 2004 Jul 27.
We examined the efficacy of the liposoluble iron chelator 2,2'-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1alpha (HIF-1alpha) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (+100%) and HIF-1alpha (-50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia.
我们研究了脂溶性铁螯合剂2,2'-联吡啶（DP）在减轻大鼠脑缺血组织损伤方面的疗效以及潜在细胞保护作用的相关机制。为此，在大鼠诱导皮层光血栓性血管闭塞前15分钟和闭塞后1小时腹腔注射DP（20mg/kg）。进行组织学研究以评估梗死体积（缺血后第1天和第3天）和星形胶质细胞激活情况（缺血后第3天）。分别通过定量测量伊文思蓝外渗和N-乙酰天门冬氨酸水平，在缺血后第1天评估内皮细胞和神经元细胞的损伤。在光血栓形成后15分钟至2小时内，通过激光多普勒血流仪记录缺血核心区域的脑血流量。在缺血后4小时，通过测量脑谷胱甘肽浓度评估活性氧（ROS）的产生。在缺血后第1天通过蛋白质免疫印迹法分析血红素加氧酶-1（HO-1）和缺氧诱导因子-1α（HIF-1α）蛋白的皮层表达。DP治疗可显著减少梗死体积以及内皮细胞和神经元细胞的缺血损伤。这种细胞保护作用与ROS产生减少、灌注不足和星形胶质细胞激活减少有关。DP治疗还导致缺血核心区域HO-1（增加100%）和HIF-1α（减少50%）蛋白表达发生显著变化。这些结果表明脂溶性铁螯合剂DP在减轻永久性局灶性缺血诱导的组织损伤方面具有疗效。
