肌萎缩侧索硬化小鼠脊髓铁离子浓度及铁离子螯合剂的神经保护作用  

Dysregulation of iron of amyotrophic lateral sclerosis mice and neuroprotective effects of iron chelator

作　　者：王倩[1] 张晓洁[1] 乐卫东[1] 

机构地区：[1]上海交通大学医学院附属瑞金医院神经病学研究所,上海200025

出　　处：《中国新药与临床杂志》2009年第11期825-830,共6页Chinese Journal of New Drugs and Clinical Remedies

摘　　要：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。AIM To observe the change of iron accumulation in spinal cords of amyotrophic lateral sclerosis （ALS） mice and the neuroprotective effects, and mechanism of iron chelators in the mice model. METHODS After iron chelators VK-28 or M30 administration, the onset of morbidity and life span of the transgenic mice was observed, the levels of iron and MDA and the activity of SOD in spinal cords of SOD1- G93A mice and wide type （WT） mice were assessed by using proper kits, and spinal motor neuron and active glias were counted by speetrophotometry. RESULTS The iron levels in spinal cords of SOD1-G93A transgenie mice were significantly increased compared with WT mice at age of 90 d （42%, P 〈 0.05） and 120 d （82%, P 〈 0.01）. And it was attenuated by iron chelators VK-28 and M30 at the age of 90 d （μg·g^-1 protein, 1 784 ± s 132, 2 103±983vs. 2398±243; bothP〈0.05） and 120d （μg·g^-1 protein, 2080± 118, 2483± 134 vs. 3 180 ± 201 ; both P 〈 0.01）. Compared with the SOD1-G93A control group, VK-28 and M30 significantly delayed the onset of morbidity （（116.2 ± 4.4） d, （110.5 ± 3.7） d vs. （104.5 ± 1.7）; both P〈 0.05） and extended the survival （（139.3 ± 3.9） d, （134.6 ± 2.1） d vs. （126.5±2.2） d; P〈 0.01, P〈 0.05）, accompanied by a significant reduction of motor neuron loss （P 〈 0.01）. Moreover, the chelators reversed the increased MDA level and the decreased SOD activity （P 〈 0.05, P 〈 0.01）, and suppressed the activation of microglia （P 〈 0.01） and astrocytes （P 〈 0.01）. CONCLUSION There were increased iron accumulation in spinal cord of SOD1-G93A transgenic mice. Iron chelators VK-28 and M30 therapy may have neuroproteetive potential for ALS by decreasing the levels of iron and oxygen free radicals in the spinal cords.

关 键 词：肌萎缩侧索硬化 活性氧 铁 铁螯合剂 神经保护药 

分 类 号：R961[医药卫生—药理学]