去铁胺对大鼠脑出血后小胶质细胞活化的抑制及其继发性神经损伤的保护作用

Deferoxamine suppresses microglia activation and protects against secondary neural injury after intracerebral hemorrhage in rats

目的观察铁螯合剂去铁胺(DFA)对脑出血(ICH)后小胶质细胞活化的抑制及其继发性神经损伤的保护作用。方法随机将大鼠分为假手术组、ICH组和DFA治疗组,利用胶原酶制备大鼠基底节区ICH模型,术后1 h开始每12 h腹腔注射DFA,共7 d。测定给药后不同时间点血肿周围脑组织的铁离子浓度变化。OX42免疫组织化学染色观察血肿周围脑组织小胶质细胞变化。ELISA方法测定脑组织IL-1β和TNF-α含量变化。神经功能缺失评分和Nissl染色观察DFA处理后大鼠神经功能恢复和神经元丢失情况。结果 ICH后3 d开始,血肿周围脑组织铁离子浓度较假手术组动物显著增高,并可持续至28 d,同时伴随有局部小胶质细胞数量的显著性增加。应用DFA后,显著降低了血肿周围脑组织的铁离子浓度,且小胶质细胞的数量显著减少,活化小胶质细胞分泌的神经毒性细胞因子IL-1β和TNF-α含量显著降低。同时,血肿周围组织神经元的丢失显著减少,神经功能缺失评分显著降低。结论 ICH后血肿持续释放的铁离子可激活局部小胶质细胞,造成继发性脑损伤。DFA通过清除血肿周围脑组织的铁离子,抑制小胶质细胞的过度活化,减少ICH的神经元死亡,从而改善继发性神经功能障碍。

Objective To investigate the effect of the iron chelator deferoxamine （DFA） in suppressing microglia activation and protecting against secondary neural injury in a rat model of intracerebral hemorrhage （ICH）. Methods SD rats were randomly divided into sham-operated group, ICH group and DFA treatment group. ICH model was established by infusion of type IV collagenase into the right basal ganglia, and starting from 1 h after the operation, the rats received intraperitoneal DFA injections every 12 h for 7 days. The iron content in the perihematoma brain tissue was determined at different time points after DFA administration, and OX42 immunohistochemistry was used to observe the changes in the microglia. The contents of interleukin-1β （IL-1β） and tumor necrosis factor-a （TNF-a） in the brain tissue were detected by ELISA. The neural death and neurological deficiency were measured using Nissl staining and neurological scores, respectively. Results The iron content in the brain tissues around the hematoma was significantly increased 3 days after ICH and maintained a high level till 28 days, accompanied by a marked increase of microglial cells as compared to the sham-operated group. DFA injection caused significantly decreased iron content in the brain tissue, reduced number of microglial cells, and lowered levels of IL-1β and TNF-a. Neuronal loss around the hematoma was obviously reversed after DFA injections, which resulted in improved neurological deficiency. Conclusion DFA can suppress microglia activation by removing iron overload from the perihematoma brain tissue, thus reducing secondary neuronal death and neurological deficiency in rats with ICH.