Sengstock G J, Olanow C W, Menzies R A, Dunn A J, Arendash G W
Department of Biology, University of South Florida, Tampa 33620.
J Neurosci Res. 1993 May 1;35(1):67-82. doi: 10.1002/jnr.490350109.
Iron has recently been suggested to contribute to the pathogenesis of Parkinson's disease (PD) because of the finding of increased iron levels in the substantia nigra pars compacta (SNc) above those of control patients. Iron is capable of catalyzing numerous reactions which could lead to free radical formation and oxidative damage to DNA, proteins, lipid membranes, and other biological molecules. Neurodegeneration in the SNc of the PD brain may be a consequence of increased iron, which promotes these cytotoxic reactions. To test whether excess iron could play a causative role in the degeneration of nigral neurons, we infused 1.25-6.3 nmol of iron into the rat substantia nigra (SN) unilaterally utilizing two different infusion protocols. All infusates were isosmotic and pH-balanced in a citrate-bicarbonate vehicle. Animals were decapitated at either 1 or 2 months postinfusion. Striatal tissue was assayed for biogenic amines by HPLC and the remaining brainstem was processed for histological analysis. Iron-stained coronal sections revealed 1) no left/right staining difference with vehicle infusion, 2) a dose-dependent iron accumulation in the infused SN that was restricted to the zona compacta and dorsal-most zona reticularis when the lowest iron concentration was infused, and 3) a dose-dependent reduction in SN volume. Thionine-stained sections revealed neuronal loss and accompanying reactive gliosis within an area that corresponded closely to that of increased iron staining. These degenerative changes were more extensive in animals infused via a side-by side vs. a sequential protocol. Neurochemically, there was a highly significant correlation between the amount of iron infused intranigrally and magnitude of reductions in striatal DA, DOPAC, and HVA within the ipsilateral striatum. These data indicate that iron infusion into the SN can cause degenerative changes within the SN and that these changes can be restricted to the SNc region when low amounts of iron are infused. The data further support the hypothesis that iron-induced degeneration may contribute to the pathogenesis of PD.
最近有研究表明，帕金森病（PD）的发病机制可能与铁有关，因为在黑质致密部（SNc）发现患者铁水平高于对照组。铁能够催化众多反应，这些反应可能导致自由基形成，并对DNA、蛋白质、脂质膜和其他生物分子造成氧化损伤。PD患者大脑SNc中的神经退行性变可能是铁含量增加的结果，而铁会促进这些细胞毒性反应。为了测试过量的铁是否在黑质神经元变性中起因果作用，我们采用两种不同的注射方案，将1.25 - 6.3 nmol的铁单侧注入大鼠黑质（SN）。所有注入物在柠檬酸盐 - 碳酸氢盐载体中均为等渗且pH平衡。在注射后1或2个月将动物断头。通过高效液相色谱法（HPLC）检测纹状体组织中的生物胺，并对其余脑干进行组织学分析。铁染色冠状切片显示：1）注入载体时左右染色无差异；2）当注入最低铁浓度时，注入的SN中铁积累呈剂量依赖性，且仅限于致密带和最背侧的网状带；3）SN体积呈剂量依赖性减小。硫堇染色切片显示，神经元丢失并伴有反应性胶质增生，其区域与铁染色增加的区域密切对应。与依次注射方案相比，采用并排注射方案的动物中这些退行性变化更为广泛。神经化学方面，向黑质内注入的铁量与同侧纹状体内纹状体多巴胺（DA）、3,4 - 二羟基苯乙酸（DOPAC）和高香草酸（HVA）减少的幅度之间存在高度显著的相关性。这些数据表明，向SN注入铁可导致SN内的退行性变化，当注入少量铁时，这些变化可局限于SNc区域。这些数据进一步支持了铁诱导的变性可能导致PD发病机制的假说。
