格尔德霉素对脑缺血／再灌注神经损伤保护作用的机制研究

Research on the protective effects of geldanamycin on nerve injury after cerebral ischemia/reperfusion

目的探讨格尔德霉素在大鼠脑缺8／再灌注神经损伤保护中的分子机制。方法清洁级SD大鼠，建立四动脉结扎法大鼠脑缺血模型。SD大鼠随机分组，每组6只：①Sham组，仅手术，不进行缺血／再灌注；②脑缺血／再灌注6h组（I／R组）；③溶剂对照组（D＋I／R组），缺血前20min溶剂20μl／kg脑室注射；④格尔德霉素组（G＋I／R组），缺血前20min格尔德霉素20μl／kg脑室注射。采用免疫组化和免疫印迹技术检测格尔德霉素对脑缺血／再灌注后HSP90的表达和P38蛋白激酶的磷酸化水平。结果再灌注6h的格尔德霉素组HSP90的蛋白表达量和P38的磷酸化水平与I／R组相比较显著降低（P〈0．05）。结论格尔德霉素通过抑制HSP90的表达及P38蛋白激酶的磷酸化发挥缺血／再灌注脑损伤保护作用。

Objective To investigate the molecular mechanism of geldanamycin to prevent rat nerve injury after cerebral isehemia/reperfnsion. Methods Adult male Sprague - Dawley rats weighing 250 - 300 g were adopted to establish a cerebral ischemia model through occlusions of bilateral common carotid and vertebral arteries. These animals were randomly divided into the following groups （n = 6） ： a sham operation group, an I/R group, a solvent group which was injected with 20 μl/kg solvent 20 min before ischemia, and a geldanamycin group which was injected with 20μ/kg geldanamycin 20 rain before ischemia. Then, the levels of HSP90 and phosphorylated P38 kinase in the hippocampus were measured by immunohistochemistry and western blotting. Results After reperfusion for 6 h, the geldanamycin group produced obviously decreased levels of HSP90 and phosphorylated P38 kinase than the I/R group （ P 〈 0.05 ）. Conclusion Geldanamycin can exert neuroprotective effects through inhibiting the amount of HSP90 and blocking the phosphorylation of P38 kinase.