局部应用重组水蛭素对脑出血模型大鼠血肿周边组织损伤的干预作用

Effect of local recombinant hirudin administration on perihematomal tissue injuries in rat models of intracerebral hemorrhage

目的 探讨脑出血后局部应用凝血酶特异抑制剂———重组水蛭素治疗血肿周边组织损伤的价值和治疗时间窗。方法 采用自体血注入方法建立大鼠脑出血模型 ,分别于 5 0 μl自体血注入同时、3h后以及 9h后血肿内给予 10U重组水蛭素干预 ,术后 72h记录大鼠神经功能缺损评分 (neurologicaldeficitscore ,NDS) ,检测血肿周边组织髓过氧化物酶 (MPO)的活性、脑水含量及TUNEL阳性细胞数量的变化 ,并通过检测血红蛋白含量评价水蛭素对血肿容量的影响。结果 脑出血同时及 3h后给予水蛭素可显著减轻大鼠神经功能缺损 ,降低局部MPO活性、减少脑水含量及TUNEL阳性细胞数量 ,9h后给予水蛭素仍可减轻局部组织脑水含量。与出血组比较 ,局部应用水蛭素未导致血肿红蛋白含量增加。结论 脑出血后早期 (9h内 )局部应用水蛭素可减轻血肿周边组织的白细胞浸润、脑水肿和细胞死亡 ,且无明显再出血副作用 ,抗凝血酶治疗有可能成为防治出血性脑损伤的有效措施之一。

Objective To investigate the time window and the value of anti-thrombin therapy to perihematomal tissue injuries in rat models of intracerebral hemorrhage (ICH) with a special thrombin inhibitor—recombinant hirudin. Methods Rats ICH models were established by 50μl autologous blood injection. Recombinant hirudin was injected into hematoma immediately,or at 3h and 9h after blood injection. 72h later,all rats were decapitated after neurological deficit scores were evaluated,then brain water content and MPO activities were measured and the expression of TUNEL positive cells in perihematoma were detected. To verify whether hemorrhage volume could be increased by hirudin,hemoglobin content was measured. Results TUNEL positive cells,brain water content,and MPO activities in perihematoma all increased strongly 3d after ICH(P< 0.01). All of the three were decreased significantly whether recombinant hirudin was injected immediately or at 3h after ICH(P< 0.01 or P< 0.05). There was no significant change of TUNEL positive cells and MPO activities in perihematoma except brain water content if recombinant hirudin was injected at 6h after ICH. Recombinant hirudin locally used did not change hematoma volume in ICH models. Conclusion Thrombin takes a role in perihematomal tissue injuries in intracerebral hemorrhage. The infiltration of leukocyte,cell death in perihematoma and brain water content could be reduced if recombinant hirudin was given within 9h after ICH without adverse affects such as rebleeding. Therefor,it might be one of the effective measures to prevent brain injuries in ICH if anti-thrombin therapy has been considered.