促红细胞生成素改善慢性脑缺血大鼠空间学习记忆能力的机制探讨

Mechanisms of Erythropoietin relieve hypoperfusion induced spatial learning and memory impairment in chronic cerebral ischemic rats

目的:观察促红细胞生成素(EPO)对慢性脑缺血大鼠空间记忆障碍的改善作用并探讨其作用机制。方法:采用结扎大鼠双侧颈总动脉的方法建立慢性脑缺血模型,术后常规饲养3 m后,连续给予EPO 1 000 U/kg腹腔注射,持续1 w。3 w后应用Morris水迷宫观察大鼠空间记忆能力,采用免疫组织化学和免疫荧光观察海马齿状回神经细胞增殖及凋亡状况。结果:慢性脑缺血可导致大鼠空间学习记忆能力损伤,与假手术组相比,2VO+saline组大鼠空间学习能力显著降低,P<0.01;给予EPO干预后较生理盐水处理组有所改善,P<0.05。免疫荧光结果提示慢性脑缺血后大鼠齿状回凋亡神经细胞较假手术组增多,(19.50±3.52)/0.1 mm2 VS(9.58±2.43)/0.1 mm2,P<0.01;给予EPO治疗后,神经细胞凋亡减少,(13.17±2.25)/0.1 mm2 VS(19.50±3.52)/0.1 mm2,P<0.05。免疫组织化学结果显示慢性脑缺血后大鼠海马齿状回神经细胞增殖较假手术组增多,(6.46±0.82)/0.1 mm2 VS(3.59±0.73)/0.1 mm2,P<0.05;EPO治疗组比生理盐水处理组更加明显,(8.24±0.89)/0.1 mm2 VS(6.46±0.82)/0.1 mm2,P<0.05。结论:EPO可通过促进神经细胞增殖、减少神经细胞凋亡改善慢性脑缺血导致的大鼠空间记忆能力损伤。

Objective：To study preserve effect and mechanisms of erythropoietin（EPO） on spatial learning and memory in chronic cerebral ischemic rats.Methods：The chronic cerebral ischemia models were made by permanent bilateral occlusion of both common carotid arteries（2VO）.After the surgery,rats were routinely bred for 3month,1000U/kg EPO was intraperitoneal injected for 1 week.3 weeks later,Morris water maze test was carried out to evaluate the spatial learning and memory,immunohistochemistry and immunofluorescence were used to study apoptosis and cell proliferation in hippocampal dentate gyrus.Results： Chronic cerebral ischemia could induce spatial learning and memory impairment,P0.01,administration of EPO can improve rats performance in water maze,P0.05.Results from immunofluorescence indicate that chronic cerebral ischemia induced cell apoptosis in hippocampal dentate gyrus,（19.50±3.52）/0.1 mm2 VS（9.58±2.43）/0.1 mm2,P0.01,rats received EPO treatment with less apoptosis cells than saline-treated rats,（13.17±2.25）/0.1 mm2 VS（19.50±3.52）/0.1 mm2,P0.05.Immunohistochemisty results revealed that chronic cerebral ischemia could promote cell proliferation in surgical rats,（6.46±0.82）/0.1 mm2 VS（3.59±0.73）/0.1 mm2,P0.05,the phenomenon was more obvious in EPO treated rats,（8.24±0.89）/0.1 mm2 VS（6.46±0.82）/0.1 mm2,P0.05.Conclusions： EPO relieves hypoperfusion induced spatial learning and memory impairment by promote cell proliferation and reduce cell apoptosis in chronic cerebral ischemia rats.