Enochs W S, Sarna T, Zecca L, Riley P A, Swartz H M
University of Illinois College of Medicine, Urbana.
J Neural Transm Park Dis Dement Sect. 1994;7(2):83-100. doi: 10.1007/BF02260963.
A characteristic feature of both Parkinson's disease (idiopathic paralysis agitans) and normal aging is loss of pigmented neurons in the substantia nigra. This has been found to correlate with the accumulation of neuromelanin and with oxidative stress in this brain region, but a clear association between these factors has not been established. Based on our recent demonstration that neuromelanin is a true melanin, containing bound metal ions in situ, we present a general model for its accumulation in vivo and the hypotheses (1) that it has a cytoprotective function in the sequestration of redox-active metal ions under normal conditions but (2) that it has a cytotoxic role in the pathogenesis of Parkinson's disease. Thus, neuromelanin accumulates normally through the autooxidation of catecholamines and serves tightly to bind redox-active metal ions, processes which would accelerate under conditions of intracellular or extracellular oxidative stress. Based on the known properties of melanin, however, neuromelanin also has the potential for exacerbating oxidative stress, eg by generating H2O2 when it is intact or by releasing redox-active metal ions if it loses its integrity; these reactions also would modulate the reactivity of the neuromelanin. By overwhelming intracellular antioxidative defense mechanisms, such a positive-feedback cycle could turn a condition of chronic or repeated oxidative stress in vulnerable neurons into an acute crisis, leading to cellular death. If the cumulative stress in duration and/or degree is severe enough, neuronal depletion could be sufficient to cause Parkinson's disease during life. One possible trigger for this cascade is suggested by the increased nigral iron contents in postmortem parkinsonian brains and the correlation of this disease with urban living where exposure to heavy metal ions is high: the saturation of neuromelanin with redox-active metal ions. Parkinson's disease therefore may be a form of accelerated aging in the substantia nigra associated with environmental toxins in which neuromelanin has a central, active role.
帕金森病（特发性震颤麻痹）和正常衰老的一个共同特征是黑质中色素神经元的丧失。研究发现，这与神经黑色素的积累以及该脑区的氧化应激相关，但这些因素之间尚未建立明确的关联。基于我们最近的研究表明神经黑色素是一种真正的黑色素，原位含有结合的金属离子，我们提出了一个其在体内积累的通用模型以及以下假设：（1）在正常条件下，它在螯合具有氧化还原活性的金属离子方面具有细胞保护功能；（2）在帕金森病的发病机制中，它具有细胞毒性作用。因此，神经黑色素通常通过儿茶酚胺的自动氧化而积累，并紧密结合具有氧化还原活性的金属离子，这些过程在细胞内或细胞外氧化应激条件下会加速。然而，根据黑色素的已知特性，神经黑色素也有可能加剧氧化应激，例如当其完整时产生过氧化氢，或者当其失去完整性时释放具有氧化还原活性的金属离子；这些反应也会调节神经黑色素的反应性。通过压倒细胞内的抗氧化防御机制，这样一个正反馈循环可能会将脆弱神经元中的慢性或反复氧化应激状态转变为急性危机，导致细胞死亡。如果持续时间和/或程度上的累积应激足够严重，神经元的耗竭可能足以在生命过程中引发帕金森病。死后帕金森病患者大脑中黑质铁含量的增加以及该疾病与重金属离子暴露较高的城市生活之间的相关性，提示了这种级联反应的一个可能触发因素：神经黑色素被具有氧化还原活性的金属离子饱和。因此，帕金森病可能是黑质中与环境毒素相关的一种加速衰老形式，其中神经黑色素起着核心的、积极的作用。
