Ben-Shachar D, Eshel G, Riederer P, Youdim M B
Department of Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Ann Neurol. 1992;32 Suppl:S105-10. doi: 10.1002/ana.410320718.
Recent studies in Parkinson's disease suggest that the degeneration of the nigrostriatal melanin-containing dopaminergic neurons results from toxic effects of free radicals, which are generated during dopamine metabolism in the substantia nigra (SN). This has been linked to the selective accumulation of iron, a known catalyst of radical formation, in the zona compacta of the SN. We have shown that interaction of iron with melanin may result in a high affinity binding of iron to melanin (KD = 13.0 +/- 0.15 nM). Indeed, x-ray analysis of melanized dopamine neurons of parkinsonian SN has shown an interaction of iron with melanin that is absent in control brains. In the presence of excess Fe3+, melanin potentiates iron-induced lipid peroxidation. Since iron chelators prevent lipid peroxidation, we have ascertained the ability of the iron chelator deferoxamine to prevent the lesion of the nigrostriatal dopamine neuron induced by 6-hydroxy dopamine (6-OHDA). Our results demonstrated that intraventricular injection of 130 ng deferoxamine to rats prior to 250 micrograms of 6-OHDA partially prevented the decrease in striatal dopamine content caused by 6-OHDA (56% reduction vs 90%, respectively). This protection was sufficient to produce normal dopamine-related behavioral responses. These results suggest that iron and iron chelators play a crucial role in the process of dopaminergic neurodegeneration and neuroprotection. The latter is further supported by our recent findings that intranigral injection of iron (50 micrograms) resulted in a substantial selective decrease of striatal dopamine (95%) and impaired dopamine-related responses.
近期关于帕金森病的研究表明，黑质纹状体含黑色素的多巴胺能神经元的退化是由自由基的毒性作用导致的，这些自由基在黑质多巴胺代谢过程中产生。这与铁（一种已知的自由基形成催化剂）在黑质致密部的选择性蓄积有关。我们已经表明，铁与黑色素的相互作用可能导致铁与黑色素的高亲和力结合（解离常数KD = 13.0 +/- 0.15 nM）。事实上，对帕金森病患者黑质中黑色素化多巴胺神经元的X射线分析显示，铁与黑色素之间存在相互作用，而在对照脑中则不存在这种相互作用。在存在过量Fe3+的情况下，黑色素会增强铁诱导的脂质过氧化。由于铁螯合剂可防止脂质过氧化，我们已确定铁螯合剂去铁胺预防6-羟基多巴胺（6-OHDA）诱导的黑质纹状体多巴胺神经元损伤的能力。我们的结果表明，在注射250微克6-OHDA之前，向大鼠脑室内注射130纳克去铁胺可部分预防6-OHDA引起的纹状体多巴胺含量下降（分别为56%的降低与90%的降低）。这种保护足以产生正常的多巴胺相关行为反应。这些结果表明，铁和铁螯合剂在多巴胺能神经退行性变和神经保护过程中起关键作用。我们最近的研究结果进一步支持了后者，即向黑质内注射铁（50微克）会导致纹状体多巴胺大量选择性减少（95%）并损害多巴胺相关反应。
