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目的探讨肌萎缩侧索硬化(ALS)小鼠脊髓中铁离子的异常变化和铁离子螯合剂的神经保护作用及其可能机制。方法SOD1-G93A转基因小鼠腹腔注射铁离子螯合剂VK-28(5mg·kg-1)及M30(5mg·kg-1)后,记录小鼠发病及生存时间的改变。试剂盒测定脊髓组织中铁离子和丙二醛(MDA)浓度及超氧化物歧化酶(SOD)活性。显微镜下观察脊髓运动神经元的状态及胶质细胞的激活。结果与正常对照组小鼠相比,90和120日龄转基因小鼠的脊髓中铁离子浓度分别增高42%(P<0.05)和82%(P<0.01)。与转基因模型组相比,铁离子螯合剂VK-28和M30能够降低铁离子浓度(μg·g-1蛋白,90d:1784±s132,2103±983vs.2398±243,均P<0.05;120d:2080±118,2483±134vs.3180±201,均P<0.01),延迟其发病时间[(116±4)d,(110±4)dvs.(104.5±1.7)d;均P<0.05]及其生存期[(139±4)d,(134.6±2.1)dvs.(126.5±2.2)d;P<0.01,P<0.05],并使小鼠脊髓前角运动神经元存活的数目明显增多(P<0.01),减少脊髓组织中增多的MDA并使降低的SOD活性增加(P<0.05,P<0.01),以及抑制星形胶质细胞和小胶质细胞的激活(P<0.01)。结论SOD1-G93A转基因ALS小鼠脊髓组织铁离子浓度升高,VK-28及M30可能通过降低脊髓内异常升高的铁离子浓度和减少氧离子自由基而发挥神经保护作用。
Objective To investigate the abnormal changes of iron ion in spinal cord of amyotrophic lateral sclerosis (ALS) mice and the neuroprotective effect of iron chelator and its possible mechanism. Methods The SOD1-G93A transgenic mice were injected intraperitoneally with iron chelator VK-28 (5mg · kg-1) and M30 (5mg · kg-1). The incidence and survival time of mice were recorded. The concentration of iron and malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in spinal cord tissue were determined by kit. The condition of spinal motoneurons and the activation of glial cells were observed under microscope. Results Compared with the normal control group, the iron concentrations in the spinal cord increased by 42% (P <0.05) and 82% (P <0.01), respectively, in the 90th and 120th day old transgenic mice. Compared with the transgenic model group, the iron chelators VK-28 and M30 could reduce the iron concentration (μg · g-1 protein, 90d: 1784 ± s132, 2103 ± 983vs.2398 ± 243, all P <0.05; (P <0.01), and delayed the onset time (116 ± 4) d and (110 ± 4) dvs. (104.5 ± 1.7) d, respectively; all P <0.05] (139 ± 4) d, (134.6 ± 2.1) dvs. (126.5 ± 2.2) d, P <0.01, P <0.05], and significantly increased the numbers of surviving neurons in the anterior horn of spinal cord in mice P <0.01), decreased MDA in spinal cord tissue and decreased the activity of SOD (P <0.05, P <0.01), and inhibited the activation of astrocytes and microglia (P <0.01). Conclusion The concentration of Fe 2+ in the spinal cord of SOD1-G93A transgenic ALS mice increased. VK-28 and M30 may exert neuroprotective effect by decreasing the concentration of iron ion in the spinal cord and decreasing the free radicals of oxygen ions.