Pedchenko T V, LeVine S M
Department of Molecular and Integrative Physiology and the Smith Mental Retardation and Human Development Center, University of Kansas Medical Center, Kansas City 66160, USA.
J Neuroimmunol. 1998 Apr 15;84(2):188-97. doi: 10.1016/s0165-5728(97)00256-7.
Data from several studies indicate that free radicals have a pathogenic role in experimental allergic encephalomyelitis (EAE). Iron can contribute to free radical damage by catalyzing the formation of hydroxyl radical, inducing secondary initiation of lipid peroxidation and by promoting the oxidation of proteins. The iron chelator, desferrioxamine, can limit these oxidative reactions and it can scavenge peroxynitrite independent of iron chelation. Two previous studies have examined the therapeutic value of desferrioxamine in EAE. One study observed an effect when disease was induced by spinal cord homogenates (J. Exp. Med. 160, p. 1532, 1984), but a second study found no therapeutic value of desferrioxamine for myelin basic protein (MBP)-induced EAE (J. Neuroimmunol. 17, p. 127, 1988). In the second study, the drug was only administered during the preclinical stages of disease. Since desferrioxamine scavenges free radicals and prevents their formation, we hypothesized that the drug should be given during the active stage of disease to have therapeutic value. We first demonstrated that the drug enters the CNS around inflammatory cells in EAE animals. In animals treated during the active stage of MBP-induced EAE, the clinical signs were significantly reduced compared to vehicle-treated animals. The iron-bound form of this drug, ferrioxamine, was without therapeutic value. A derivative of desferrioxamine, hydroxylethyl starch (HES)-desferrioxamine, has a greater plasma half-life than desferrioxamine and it was also tested. Although there was a suggestion of improvement in these animals, the effects were less than that observed for desferrioxamine which may be related to the greater molecular size of HES-desferrioxamine. In summary, these data suggest that chelation of iron is an effective therapeutic target for EAE.
多项研究的数据表明，自由基在实验性自身免疫性脑脊髓炎（EAE）中具有致病作用。铁可通过催化羟自由基的形成、诱导脂质过氧化的二次引发以及促进蛋白质氧化来导致自由基损伤。铁螯合剂去铁胺可限制这些氧化反应，并且它可以独立于铁螯合作用清除过氧亚硝酸盐。此前已有两项研究探讨了去铁胺在EAE中的治疗价值。一项研究观察到，当用脊髓匀浆诱导疾病时（《实验医学杂志》第160卷，第1532页，1984年），去铁胺有效果，但另一项研究发现去铁胺对髓鞘碱性蛋白（MBP）诱导的EAE没有治疗价值（《神经免疫学杂志》第17卷，第127页，1988年）。在第二项研究中，该药物仅在疾病的临床前期给药。由于去铁胺可清除自由基并防止其形成，我们推测该药物应在疾病的活动期给药才具有治疗价值。我们首先证明该药物可进入EAE动物炎症细胞周围的中枢神经系统。在MBP诱导的EAE活动期接受治疗的动物中，与接受载体治疗的动物相比，临床症状明显减轻。该药物的铁结合形式，即铁胺，没有治疗价值。去铁胺的一种衍生物，羟乙基淀粉（HES）-去铁胺，其血浆半衰期比去铁胺长，也进行了测试。尽管这些动物有改善的迹象，但其效果不如去铁胺，这可能与HES-去铁胺更大的分子大小有关。总之，这些数据表明铁螯合是EAE的一个有效治疗靶点。
